2016 Group Project 6 - Revision history

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	<references/>		<references/>

	{{~~student image~~}}		{{Student Image}}

	[[Category:TGF-beta]]		[[Category:TGF-beta]]

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	\| '''BMP'''		\| '''BMP'''
	\| Bone Morphogenetic Protein, a protein part of the TGF-β superfamily.		\| Bone Morphogenetic Protein, a protein part of the TGF-β superfamily.
			\|}

			<references/>


			[[Category:TGF-beta]]

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	==Introduction==		==Introduction==

	The transforming growth factor beta (TGF-β) is a multifunctional and pleiotropic cytokine ~~<ref><pubmed>~~26555259~~</pubmed></ref>.~~		The transforming growth factor beta (TGF-β) is a multifunctional and pleiotropic cytokine.{{#pmid:26555259\|PMID26555259}}
	The TGF-β signalling pathway is crucial to the control of different biological and pathological processes, such as cellular proliferation and differentiation, angiogenesis, immune regulation/inflammation, apoptosis and cell survival. ~~<ref><pubmed>~~17896911~~</pubmed></ref>~~		The TGF-β signalling pathway is crucial to the control of different biological and pathological processes, such as cellular proliferation and differentiation, angiogenesis, immune regulation/inflammation, apoptosis and cell survival.{{#pmid:17896911\|PMID17896911}}
	TGF-β belongs to the Transforming Growth Factor superfamily - a large group of structually connected cell regulatory proteins. It consists of TGF-β 1, 2 AND 3, Growth Differentiation Factors (GDFs), Activins, Inhibins, Bone Morphogenetic Proteins (BMPs), Glial-derived Neurotrophic Factors (GDNFs) and Mullierian Inhibiting Substance (MIS). ~~<ref><pubmed>~~24270394~~</pubmed></ref>~~
	Most importantly, TGF-β plays a dominant part in the development of the embryo and adult organism. ~~<ref><pubmed>~~23926286~~</pubmed></ref>~~		TGF-β belongs to the Transforming Growth Factor superfamily - a large group of structually connected cell regulatory proteins. It consists of TGF-β 1, 2 AND 3, Growth Differentiation Factors (GDFs), Activins, Inhibins, Bone Morphogenetic Proteins (BMPs), Glial-derived Neurotrophic Factors (GDNFs) and Mullierian Inhibiting Substance (MIS).{{#pmid:24270394\|PMID24270394}}
			Most importantly, TGF-β plays a dominant part in the development of the embryo and adult organism.{{#pmid:23926286\|PMID23926286}}

	This wiki aims to present a helpful overview of the TGF-β signalling pathway, but is in no means a complete resource on all information regarding the topic. This site focuses on particular aspects of the pathway, such as its history, process, regulation, significance in embryonic development, animal studies and abnormalities.		This wiki aims to present a helpful overview of the TGF-β signalling pathway, but is in no means a complete resource on all information regarding the topic. This site focuses on particular aspects of the pathway, such as its history, process, regulation, significance in embryonic development, animal studies and abnormalities.
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	\| '''1988'''		\| '''1988'''
	\| The process of maturation of follicle-enclosed oocytes and cumulus-oocyte complexes was sped up by TGF beta. It was discovered that TGF beta and other growth factors are effective in vitro stimulators of oocyte maturation in the rat		\| The process of maturation of follicle-enclosed oocytes and cumulus-oocyte complexes was sped up by TGF beta. It was discovered that TGF beta and other growth factors are effective in vitro stimulators of oocyte maturation in the rat
	~~<ref><pubmed>~~3275534~~</pubmed></ref>~~		{{#pmid:3275534\|PMID3275534}}
	\|-		\|-
	\| '''1989'''		\| '''1989'''
	\| It was already known that TGF-beta 1 is a strong autocrine growth inhibitor of lymphocytes. Ellingsworth and colleagues found that TGF-beta 1 binds to all three cell surface-binding proteins (280-200 kD, 95-85 kD, 65 kD).		\| It was already known that TGF-beta 1 is a strong autocrine growth inhibitor of lymphocytes. Ellingsworth and colleagues found that TGF-beta 1 binds to all three cell surface-binding proteins (280-200 kD, 95-85 kD, 65 kD).
	It was also found that these binding proteins are required for signal transduction. Overall, they discovered that the regulation of the expression of the TGF-beta 1 receptor is controlled by T cell mitogenic signals.		It was also found that these binding proteins are required for signal transduction. Overall, they discovered that the regulation of the expression of the TGF-beta 1 receptor is controlled by T cell mitogenic signals.
	~~<ref><pubmed>~~2785999~~</pubmed></ref>~~		{{#pmid:2785999\|PMID2785999}}
	\|-		\|-
	\| '''1989'''		\| '''1989'''
	\| It was made known that the properties of R mutants classify TGF-beta type I binding protein as the receptor involved in mediating TGF-beta actions on cell adhesion and proliferation		\| It was made known that the properties of R mutants classify TGF-beta type I binding protein as the receptor involved in mediating TGF-beta actions on cell adhesion and proliferation
	~~<ref><pubmed>~~2536702~~</pubmed></ref>~~		{{#pmid:2536702\|PMID2536702}}
	\|-		\|-
	\| '''1989'''		\| '''1989'''
	\| Drosophil was the only member of the TGF-beta family to be identified in invertebrates		\| Drosophil was the only member of the TGF-beta family to be identified in invertebrates
	~~<ref><pubmed>~~2699859~~</pubmed></ref>~~		{{#pmid:2699859\|PMID2699859}}
	\|-		\|-
	\| '''1990'''		\| '''1990'''
	\| It was already known that the rapid increase in number response of mink lung epithelial cells to serum and to epidermal growth factor was inhibited by TGF beta 1. A necessary component of TGF-beta 1 mediated growth inhibition in CCL64 epithelial cells is the coupling of TGF beta 1 receptor binding to G-protein activation		\| It was already known that the rapid increase in number response of mink lung epithelial cells to serum and to epidermal growth factor was inhibited by TGF beta 1. A necessary component of TGF-beta 1 mediated growth inhibition in CCL64 epithelial cells is the coupling of TGF beta 1 receptor binding to G-protein activation
	~~<ref><pubmed>~~2156499~~</pubmed></ref>~~		{{#pmid:2156499\|PMID2156499}}
	\|-		\|-
	\| '''2000'''		\| '''2000'''
	\| VegT function was found to be involved in sequence with the TGF beta pathway. Therefore, TGF beta signaling may be activated by the maternally expressed VegT to participate in endoderm determination		\| VegT function was found to be involved in sequence with the TGF beta pathway. Therefore, TGF beta signaling may be activated by the maternally expressed VegT to participate in endoderm determination
	~~<ref><pubmed>~~10640706~~</pubmed></ref>~~		{{#pmid:10640706\|PMID10640706}}
	\|-		\|-
	\| '''2005'''		\| '''2005'''
	\| Within the TGF beta superfamily, it was found that a limited number of type I and type II receptors worked together to produce specificity of action		\| Within the TGF beta superfamily, it was found that a limited number of type I and type II receptors worked together to produce specificity of action
	~~<ref><pubmed>~~15483083~~</pubmed></ref>~~		{{#pmid:15483083\|PMID15483083}}
	\|-		\|-
	\| '''2010'''		\| '''2010'''
	\| Deregulation of TGF beta signaling was reported in human psoriasis		\| Deregulation of TGF beta signaling was reported in human psoriasis
	~~<ref><pubmed>~~19710682~~</pubmed></ref>~~		{{#pmid:19710682\|PMID19710682}}
	\|-		\|-
	\| '''2015'''		\| '''2015'''
	\| It was known that TGF is required in the tumorigenicity and metastasis of bone tumour. A significant event in the activation of the TGF beta signaling pathway is the binding of transcription coactivator Yes-associated protein (YAP) to Smad transcription factors		\| It was known that TGF is required in the tumorigenicity and metastasis of bone tumour. A significant event in the activation of the TGF beta signaling pathway is the binding of transcription coactivator Yes-associated protein (YAP) to Smad transcription factors
	~~<ref><pubmed>~~27491038~~</pubmed></ref>~~		{{#pmid:27491038\|PMID27491038}}
	\|}		\|}


	[[File:Canonical and non-canonical signalling TGF beta pathways.png\|thumb\|500px\|Flowchart showing the Canonical and Non-Canonical pathways of TGF-β signalling pathway.~~<ref><pubmed>~~24393789~~</pubmed></ref>~~]]		[[File:Canonical and non-canonical signalling TGF beta pathways.png\|thumb\|500px\|Flowchart showing the Canonical and Non-Canonical pathways of TGF-β signalling pathway.{{#pmid:24393789\|PMID24393789}}]]
	===Canonical pathway===		===Canonical pathway===
	In the canonical pathway, the dormant TGF-β complex is formed when the three TGF-β ligand isoforms - TGF-B1, TGF-B2 and TGF-B3 - bind once it is synthesized as precursors. After secretion and extracellular activation, TGF-β ligands can bind to two types of receptors: the membranous TGF-β type III receptor or the TGF-β type II receptor (TGF-βRII) homodimers with high affinity.		In the canonical pathway, the dormant TGF-β complex is formed when the three TGF-β ligand isoforms - TGF-B1, TGF-B2 and TGF-B3 - bind once it is synthesized as precursors. After secretion and extracellular activation, TGF-β ligands can bind to two types of receptors: the membranous TGF-β type III receptor or the TGF-β type II receptor (TGF-βRII) homodimers with high affinity.

Z8600021: Protected "2016 Group Project 6" ([Edit=Allow only administrators] (indefinite) [Move=Allow only administrators] (indefinite))

2016-10-27T23:07:18Z

Protected "2016 Group Project 6" ([Edit=Allow only administrators] (indefinite) [Move=Allow only administrators] (indefinite))

← Older revision	Revision as of 09:07, 28 October 2016
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	==Further Reading==		==Further Reading==

			==TGF-B Signalling Pathway Quiz - How well do you know it?!==

			<quiz display=simple>

			{In what year was it discovered that a limited number of type 1 and type 2 TGF-B worked together to produce a specific action:
			\|type="()"}
			- 1989
			- 1990
			+ 2005
			- 2011
			\|\| Option C is correct. As indicated by the historic timeline, it was in 2005, that they found a limited number of type I and type II receptors worked together to produce specificity of action.

			{Which of the following occurs following TGF-B ligands binding to the type II receptor homodimers
			\|type="[]"}
			+ Dimerization with TGF-B type 1 receptor homodimers
			- Deactivation of TGF-B type 1 receptor kinase domain
			+ Signal transduction across phosphorylation of the C-terminus of receptor-regulated SMADs, 2 and 3.
			- TGF-B ligand binding to TGF-B type I receptor
			\|\| Options A and C are correct. For Option B, it results in the activation of the TGF-B type I receptor kinase domain and for Option D, it was a trick question because in the canonical pathway, there is no TGF-B type I receptor that a TGF-B ligand binds to.

			{True or False:
			\|type="()"}
			+ In the SMAD dependent pathway, the dimerized TGF-B type II receptors phosphyorylate and activates TGF-B type I receptors.
			- In the SMAD dependent pathway, the dimerized TGF-B type I receptors phosphyorylate and activates TGF-B type II receptors.
			\|\| Option A is correct. Following the ligand binding on TGF-B, the dimerized TGF-B type II receptor phosphorylates and activates TGF type I receptor, which usually leads to the recruitment and phosphorylation of different SMADs depending on the type I receptor expressed.

			{Which of the following are correct:
			\|type="[]"}
			- The negative regulation is important to amplify signalling from TGF-B like factors.
			+ “Cross-talk” is a process that involves positive modulation involving SMAD signalling by communicating with other signalling pathways
			- BAMBI interacts with only type 1 serine/threonine receptors to abolish their abilities to signal via TGF-B.
			+ TGF-B like factors themselves can trigger the induction of TGF-B ligands.
			\|\| Options B and D are correct. Option A is talking about positive regulation, whilst for Option C, BAMBI interacts with both type 1 and type 2 serine/threonine receptors, not just type 1.

			{In the embryonic development, TGF-B has been found to be involved in:
			\|type="()"}
			- Epithelial mesenchymal transformations in developing coronary vasculature
			- Regulating stem cell kinetics of the mammary gland
			- Development of the primary and secondary palate into palatal shelves
			+ All of the above
			\|\| All of the above statements are true.

			{Which of the following is true:
			\|type="[]"}
			- Loeys-Dietz syndrome causes disproportionate height and abnormally long fingers and toes.
			+ TGF-B is involved in encouraging apoptosis or inducing differentiation and thus when its pathway is affected, cells can proliferate and become cancerous as they no longer do either.
			+ It is common to find Multiple Sclerosis patients to have lower levels of TGF-B
			- TGF-B can inactivate inflammatory macrophages of the heart but not vary the matrix metabolism in a pressure-overloaded heart.
			\|\| Options B and C are correct. Option A is describing Marfan Syndrome whilst for Option D, TGF-B can accomplish both inactivating inflammatory macrophages and varying the matrix metabolism.

			</quiz>

	==Glossary==		==Glossary==

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	====Cancer====		====Cancer====
	Alterations of this signalling pathway are common in cancer. Accessory proteins such as soluble or membrane-bound regulators or co-receptors can also affect TGF-beta signalling. A normal acting cell has a functional TGF-β signalling pathway, in which TGF- β stops proliferation of cells at G1 stage to either encourage apoptosis or induce differentiation. If the TGF-β signaling pathway becomes mutated these cells can become cancerous as the TGF-β no longer controls the cell. Uncontrolled, these cancer cells proliferate and cause surrounding fibroblasts, immune cells, endothelial and smooth-muscle cells to proliferate as well. From this increased production of TGF-β it causes angiogenesis and immunosuppression, further propogating the cancer. <ref><pubmed>10793168</pubmed></ref>The human body has an regulation against this, which is called effector T-cells which destroy cancer cells via an inflammatory reaction. However, TGF-β converts them into regulatory T-cells, which reduce the inflammatory reaction.		Alterations of this signalling pathway are common in cancer. Accessory proteins such as soluble or membrane-bound regulators or co-receptors can also affect TGF-beta signalling. A normal acting cell has a functional TGF-β signalling pathway, in which TGF- β stops proliferation of cells at G1 stage to either encourage apoptosis or induce differentiation. If the TGF-β signaling pathway becomes mutated these cells can become cancerous as the TGF-β no longer controls the cell. Uncontrolled, these cancer cells proliferate and cause surrounding fibroblasts, immune cells, endothelial and smooth-muscle cells to proliferate as well. From this increased production of TGF-β it causes angiogenesis and immunosuppression, further propogating the cancer. <ref><pubmed>10793168</pubmed></ref>The human body has an regulation against this, which is called effector T-cells which destroy cancer cells via an inflammatory reaction. However, TGF-β converts them into regulatory T-cells, which reduce the inflammatory reaction.
			[[File:Embryo marfan.jpg\|thumb\|250px\|left\|Patient with Marfan syndrome. Note aesthenic or marfanoid body habitus, pronounced myopia (thick glasses), previous thoracic surgery (composite aortic root/aortic valve replacement)..<ref><pubmed> PMC1767196 </pubmed></ref>]]

	====Marfan syndrome====		====Marfan syndrome====
	[[File:Embryo marfan.jpg\|thumb\|250px\|Patient with Marfan syndrome. Note aesthenic or marfanoid body habitus, pronounced myopia (thick glasses), previous thoracic surgery (composite aortic root/aortic valve replacement)..<ref><pubmed> PMC1767196 </pubmed></ref>]]

	It is also suggested that TGF-β signaling has a large part to play in the pathogenesis of Marfan syndrome. This disease causes disproportionate height, abnormally long fingers and toes, displaced crystalline lens of the eye. Not only this but heart complications can also occur, like mitral valve prolapse or aortic enlargement. Marfan syndrome is generally known to be caused by defective creation of elastic fibres, more specifically of the glycoprotein fibrillin I. In a study done it was observed that by adding TGF-β antagonist in mice who were affected by Marfan syndrome phenotype, their symptoms were alleviated.<ref><pubmed>16601194</pubmed></ref> From this, we can see that the mechanism involved in Marfan syndrome most likely has an underlying relation with lowered sequestration of TGF-β by fibrillin.<ref><pubmed>16571647</pubmed></ref>		It is also suggested that TGF-β signaling has a large part to play in the pathogenesis of Marfan syndrome. This disease causes disproportionate height, abnormally long fingers and toes, displaced crystalline lens of the eye. Not only this but heart complications can also occur, like mitral valve prolapse or aortic enlargement. Marfan syndrome is generally known to be caused by defective creation of elastic fibres, more specifically of the glycoprotein fibrillin I. In a study done it was observed that by adding TGF-β antagonist in mice who were affected by Marfan syndrome phenotype, their symptoms were alleviated.<ref><pubmed>16601194</pubmed></ref> From this, we can see that the mechanism involved in Marfan syndrome most likely has an underlying relation with lowered sequestration of TGF-β by fibrillin.<ref><pubmed>16571647</pubmed></ref>

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	The TGF-B pathway has many effects on cardiomyocytes, mesenchymal and immune cells. Not only this, but it plays a vital role in the pathogenesis of cardiac remodeling and fibrosis. Abnormalities in this pathway can cause an overexpression of TGF-β which has been associated with fibrosis and hypertrophy in mice hearts. We see that endogenous TGF-β is capable of varying matrix metabolism in a pressure-overloaded heart. In a heart which has undergone great stress, such as myocardial infarction, TGF-β is seen to inactivate inflammatory macrophages. This allows for less of an immune response but further done by it encouraging myofibroblast transdifferentiation and matrix synthesis. Thus higher levels of TGF-β is causing more inflammatory damage and further propagating the heart disease. <ref><pubmed>21059352</pubmed></ref>		The TGF-B pathway has many effects on cardiomyocytes, mesenchymal and immune cells. Not only this, but it plays a vital role in the pathogenesis of cardiac remodeling and fibrosis. Abnormalities in this pathway can cause an overexpression of TGF-β which has been associated with fibrosis and hypertrophy in mice hearts. We see that endogenous TGF-β is capable of varying matrix metabolism in a pressure-overloaded heart. In a heart which has undergone great stress, such as myocardial infarction, TGF-β is seen to inactivate inflammatory macrophages. This allows for less of an immune response but further done by it encouraging myofibroblast transdifferentiation and matrix synthesis. Thus higher levels of TGF-β is causing more inflammatory damage and further propagating the heart disease. <ref><pubmed>21059352</pubmed></ref>

	====~~Loeys–Dietz syndrome~~====		====Multiple Sclerosis====
	~~Abnormalities~~ of ~~the TGF-β signaling can also cause Loeys–Dietz syndrome via mutations in the~~ TGF-β ~~receptor. Loeys-Deitz syndrome connective tissue disorder~~, ~~mainly in children where there are aneurisms in the aorta~~. ~~Not only~~ this~~, but the aorta can undergo dissection~~ in ~~weakened layers~~ of ~~the aortic wall~~. ~~Further, the disease~~ is labelled into four different types, since it is an autosomal dominant genetic connective tissue disorder, the groups are categorized by their genetic cause. TGFB1 and TGFB2 cause type I and II. Normally these genes allow for ~~the fruition of the body’s development and growth~~. ~~However~~, ~~when defective~~ they ~~create non-functioning proteins~~.		In Multiple Sclerosis (MS) a common observation is that patients will generally have lower levels of TGF-β, which is suspected to prevent remylentation of neurons. The reason why this is of significance is because MS results in demylentation of neurons causing severe neurological problems. TGF-β is normally responsible for regulating apoptosis of Th17 cells.<ref><pubmed>22942700</pubmed></ref>Thus when TGF-β levels decrease due to abnormalities, they are not able to be regulating Th17 cells apoptosis.[6] This then causes Th17 cells to secrete TNF-α, finally causing a demylenation of the oliodendroglial (neurons).<ref><pubmed>22189514</pubmed></ref>By having a lower amount of TGF-β we get a higer level of Th17 cells and therefore more TNFα and neuronal damage. Thus we can observe that this pathway is vital in maintaining neuronal health.

	[~~[File:LDS .jpg\|thumb\|250px\|left\|MR angiogram of the head~~, ~~shows arterial ectasia and tortuosity~~ of the ~~intracranial vessels, symptoms of Loeys-Dietz Syndrome~~<ref><pubmed>~~24393789~~</pubmed></ref>]]

	====Obesity, Diabetes and Hepatic Steatosis====		====Obesity, Diabetes and Hepatic Steatosis====
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	This was shown again in a study done where mice affected were given a systemic blockade drug for the TGF-B pathway and it was observed that they were protected from obesity, diabetes and hepatic steatosis. <ref><pubmed>21436399</pubmed></ref>		This was shown again in a study done where mice affected were given a systemic blockade drug for the TGF-B pathway and it was observed that they were protected from obesity, diabetes and hepatic steatosis. <ref><pubmed>21436399</pubmed></ref>

			[[File:LDS .jpg\|thumb\|300px\|MR angiogram of the head, shows arterial ectasia and tortuosity of the intracranial vessels, symptoms of Loeys-Dietz Syndrome<ref><pubmed>24393789</pubmed></ref>]]
	~~====Multiple Sclerosis====~~		====Loeys–Dietz syndrome====
	~~In Multiple Sclerosis (MS) a common observation is that patients will generally have lower levels~~ of ~~TGF-β~~, ~~which is suspected to prevent remylentation~~ of ~~neurons. The reason why this is~~ of ~~significance is because MS results in demylentation of neurons causing severe neurological problems. TGF~~-~~β is normally responsible for regulating apoptosis of Th17 cells.~~<ref><pubmed>~~22942700~~</pubmed></ref>~~Thus when~~ TGF-β ~~levels decrease due to abnormalities~~, ~~they~~ are ~~not able to be regulating Th17 cells apoptosis~~.~~[6] This then causes Th17 cells to secrete TNF-α~~, ~~finally causing a demylenation~~ of the ~~oliodendroglial (neurons)~~.~~<ref><pubmed>22189514</pubmed></ref>By having a lower amount~~ of ~~TGF-β we get a higer level of Th17 cells and therefore more TNFα~~ and ~~neuronal damage~~. ~~Thus we can observe that this pathway is vital in maintaining neuronal health~~.		Abnormalities of the TGF-β signaling can also cause Loeys–Dietz syndrome via mutations in the TGF-β receptor. Loeys-Deitz syndrome connective tissue disorder, mainly in children where there are aneurisms in the aorta. Not only this, but the aorta can undergo dissection in weakened layers of the aortic wall. Further, the disease is labelled into four different types, since it is an autosomal dominant genetic connective tissue disorder, the groups are categorized by their genetic cause. TGFB1 and TGFB2 cause type I and II. Normally these genes allow for the fruition of the body’s development and growth. However, when defective they create non-functioning proteins.

	==Further Reading==		==Further Reading==

Z5019526 at 15:06, 27 October 2016

2016-10-27T15:06:10Z

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	Abnormalities of the TGF-β signaling can also cause Loeys–Dietz syndrome via mutations in the TGF-β receptor. Loeys-Deitz syndrome connective tissue disorder, mainly in children where there are aneurisms in the aorta. Not only this, but the aorta can undergo dissection in weakened layers of the aortic wall. Further, the disease is labelled into four different types, since it is an autosomal dominant genetic connective tissue disorder, the groups are categorized by their genetic cause. TGFB1 and TGFB2 cause type I and II. Normally these genes allow for the fruition of the body’s development and growth. However, when defective they create non-functioning proteins.		Abnormalities of the TGF-β signaling can also cause Loeys–Dietz syndrome via mutations in the TGF-β receptor. Loeys-Deitz syndrome connective tissue disorder, mainly in children where there are aneurisms in the aorta. Not only this, but the aorta can undergo dissection in weakened layers of the aortic wall. Further, the disease is labelled into four different types, since it is an autosomal dominant genetic connective tissue disorder, the groups are categorized by their genetic cause. TGFB1 and TGFB2 cause type I and II. Normally these genes allow for the fruition of the body’s development and growth. However, when defective they create non-functioning proteins.

	[[File:LDS .jpg\|thumb\|250px\|MR angiogram of the head, shows arterial ectasia and tortuosity of the intracranial vessels, symptoms of Loeys-Dietz Syndrome<ref><pubmed>24393789</pubmed></ref>]]		[[File:LDS .jpg\|thumb\|250px\|left\|MR angiogram of the head, shows arterial ectasia and tortuosity of the intracranial vessels, symptoms of Loeys-Dietz Syndrome<ref><pubmed>24393789</pubmed></ref>]]

	====Obesity, Diabetes and Hepatic Steatosis====		====Obesity, Diabetes and Hepatic Steatosis====

Z5019526 at 14:34, 27 October 2016

2016-10-27T14:34:07Z

← Older revision		Revision as of 00:34, 28 October 2016
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	==Animal Studies==		==Animal Studies==


	===Wound healing===		===Wound healing===
	Animal studies have served as a useful way in providing pivotal information regarding the mechanisms of TGF-β action in wound healing. In fact, much of the current information on the action of TGF-β in wound healing has been acquired from animal studies using incisional and/or excisional wounding models and manipulation of TGF-β signalling by adding the exogenous TGF-β protein or anti-TGF-β neutralizing antibodies, or by genetic alteration in components of the TGF-β signalling pathway. This is due to the fact that animal models provide outstanding experimental methods for explaining molecular mechanisms by which TGF-β regulates wound-healing responses. Ultimately, it has led the development of therapeutic strategies focusing on how the TGF-β pathway can improve wound healing and scarring outcome.		Animal studies have served as a useful way in providing pivotal information regarding the mechanisms of TGF-β action in wound healing. In fact, much of the current information on the action of TGF-β in wound healing has been acquired from animal studies using incisional and/or excisional wounding models and manipulation of TGF-β signalling by adding the exogenous TGF-β protein or anti-TGF-β neutralizing antibodies, or by genetic alteration in components of the TGF-β signalling pathway.
			[[File:Destination filename.jpeg\|thumb\|550px\|Excisional wound healing in Smad 3 KO mice.<ref><pubmed>24761336</pubmed></ref>]]
			This is due to the fact that animal models provide outstanding experimental methods for explaining molecular mechanisms by which TGF-β regulates wound-healing responses. Ultimately, it has led the development of therapeutic strategies focusing on how the TGF-β pathway can improve wound healing and scarring outcome.

	~~[[File:Destination filename.jpeg\|thumb\|550px\|Excisional wound healing in Smad 3 KO mice.<ref><pubmed>24761336</pubmed></ref>]]~~
	Wound healing is an intricate physiological process distinguished by the successive overlapping stages of inflammation, proliferation and maturation. It that requires numerous growth factors, one of which includes TGF-β, which has the widest range of effects. TGF-β is a multifunctional growth factor that employs pleiotropic effects on wound healing by regulating cell differentiation, extracellular matrix production and immune modulation. The role of TGF-β signalling in wound healing was explored through examination of the development of tissue-specific expression systems for overexpression or knockout of TGF-b signalling pathway components. This study also classified that molecules might serve as molecular targets for the treatment of pathological skin conditions such as chronic wounds and excessive scarring (fibrosis).		Wound healing is an intricate physiological process distinguished by the successive overlapping stages of inflammation, proliferation and maturation. It that requires numerous growth factors, one of which includes TGF-β, which has the widest range of effects. TGF-β is a multifunctional growth factor that employs pleiotropic effects on wound healing by regulating cell differentiation, extracellular matrix production and immune modulation. The role of TGF-β signalling in wound healing was explored through examination of the development of tissue-specific expression systems for overexpression or knockout of TGF-b signalling pathway components. This study also classified that molecules might serve as molecular targets for the treatment of pathological skin conditions such as chronic wounds and excessive scarring (fibrosis).
	Exogenously added TGF-β has the potential to promote wound healing by stimulating angiogenesis, immune cell infiltration, and ECM production, and that diminishing endogenous TGF-β action reduces scarring without adversely affecting wound-healing quality.		Exogenously added TGF-β has the potential to promote wound healing by stimulating angiogenesis, immune cell infiltration, and ECM production, and that diminishing endogenous TGF-β action reduces scarring without adversely affecting wound-healing quality.
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	===TGF-β1 Null mice: An animal model for Inflammatory Disorders===		===TGF-β1 Null mice: An animal model for Inflammatory Disorders===
	Out of the number of TGF-β1 null (knockout) mice that are generated in the laboratory, it is estimated that around 60% die in utero and the 40% that survive develops normally to term. During the first 2 weeks of postnatal life, the mice appear normal and look healthy. However, after 3 to 4 weeks, they start to develop a rapid wasting syndrome, which is largely characterised by a great decrease in ~~bodt~~ weight gain in contrast with controls. At this point, the mice become inactive and appear sick with unhealthy looking fur. Some can survive up to 4 or 5 weeks. The healthy animals are separated from their mother as the mother has the responsibility to care for the sick animals. Surprisingly, it is the affected animals that have a longer life span.		Out of the number of TGF-β1 null (knockout) mice that are generated in the laboratory, it is estimated that around 60% die in utero and the 40% that survive develops normally to term. During the first 2 weeks of postnatal life, the mice appear normal and look healthy. However, after 3 to 4 weeks, they start to develop a rapid wasting syndrome, which is largely characterised by a great decrease in body weight gain in contrast with controls. At this point, the mice become inactive and appear sick with unhealthy looking fur. Some can survive up to 4 or 5 weeks. The healthy animals are separated from their mother as the mother has the responsibility to care for the sick animals. Surprisingly, it is the affected animals that have a longer life span.

	[[File:Graph depicting the body weight of TGF-β1 knockout mice compared to normal mice.png\|600px\|thumb\|left\|Graph depicting the body weight of TGF-β1 knockout mice compared to normal mice as a function of time<ref><pubmed>7856732</pubmed></ref>]]		[[File:Graph depicting the body weight of TGF-β1 knockout mice compared to normal mice.png\|600px\|thumb\|left\|Graph depicting the body weight of TGF-β1 knockout mice compared to normal mice as a function of time<ref><pubmed>7856732</pubmed></ref>]]

	All of the knockout mice have a multifocal inflammatory disease in many tissues. The heart and lungs were the organs that were affected to the greatest degree, following the stomach, colon and pancreas.		All of the knockout mice have a multifocal inflammatory disease in many tissues. The heart and lungs were the organs that were affected to the greatest degree, following the stomach, colon and pancreas.
	No lesions in the TGF-B1 knockout mice were found in the animals that died during the first week of life. The earliest lesion was seen at 8 days of age in the lung and heart.		No lesions in the TGF-B1 knockout mice were found in the animals that died during the first week of life. The earliest lesion was seen at 8 days of age in the lung and heart. It began in the heart with endocardial endothelial hypertrophy and mild infiltration of mononuclear inflammatory cells. During the next 14 days, the endocarditis became more severe and reached the myocardium and pericardium. The most dominant inflammatory cells were macrophages. Within the lung, chronic inflammatory infiltrates consist of T and B lymphocytes, including plasma cells, whereas macrophages are the primary inflammatory cell type in the heart. From day 8, it was possible to see increased expression of major histocompatibility complex class I and II proteins in pulmonary vascular endothelium, as well as an immunoblastic response in mediastinal and mandibular lymph nodes and spleen. In the absence of any pathogens, this massive inflammatory disease, together with overexpression of major histocompatibility complex class I and II proteins and overproduction of immunoglobulins by lymphocytes, offers circumstantial evidence for an autoimmune etiology.


	~~REWORD Increased adhesion of leukocytes to~~ the ~~endothelium~~ of ~~pulmonary veins is the inital lesion seen at day 8 postnatally and is soon followed by perivascular cuffing as well as~~ inflammatory ~~infiltrates in lung parenchyma~~. ~~The lesions in~~ the ~~heart begin as~~ endocarditis and ~~then progress to myocarditis~~ and ~~pericarditis~~. Within the lung, chronic inflammatory infiltrates consist of T and B lymphocytes, including plasma cells, whereas macrophages are the primary inflammatory cell type in the heart. ~~Increased~~ expression of major histocompatibility complex class I and II proteins ~~is seen~~ in pulmonary vascular endothelium as ~~early~~ as ~~day 8. An~~ immunoblastic response in mediastinal and mandibular lymph nodes and spleen ~~is also seen~~. In the absence of any pathogens, this massive inflammatory disease, together with overexpression of major histocompatibility complex class I and II proteins and overproduction of immunoglobulins by lymphocytes, offers circumstantial evidence for an autoimmune etiology.

	<ref><pubmed>7856732</pubmed></ref>		<ref><pubmed>7856732</pubmed></ref>

Z5019526 at 14:27, 27 October 2016

2016-10-27T14:27:50Z

← Older revision		Revision as of 00:27, 28 October 2016
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	[[File:Destination filename.jpeg\|thumb\|550px\|Excisional wound healing in Smad 3 KO mice.<ref><pubmed>24761336</pubmed></ref>]]		[[File:Destination filename.jpeg\|thumb\|550px\|Excisional wound healing in Smad 3 KO mice.<ref><pubmed>24761336</pubmed></ref>]]
	Wound healing is an intricate physiological process distinguished by the successive overlapping stages of inflammation, proliferation and maturation. It that requires numerous growth factors, one of which includes TGF-β, which has the widest range of effects. TGF-β is a multifunctional growth factor that employs pleiotropic effects on wound healing by regulating cell differentiation, extracellular matrix production and immune modulation. The role of TGF-β signalling in wound healing was explored through examination of the development of tissue-specific expression systems for overexpression or knockout of TGF-b signalling pathway components. This study also classified that molecules might serve as molecular targets for the treatment of pathological skin conditions such as chronic wounds and excessive scarring (fibrosis).		Wound healing is an intricate physiological process distinguished by the successive overlapping stages of inflammation, proliferation and maturation. It that requires numerous growth factors, one of which includes TGF-β, which has the widest range of effects. TGF-β is a multifunctional growth factor that employs pleiotropic effects on wound healing by regulating cell differentiation, extracellular matrix production and immune modulation. The role of TGF-β signalling in wound healing was explored through examination of the development of tissue-specific expression systems for overexpression or knockout of TGF-b signalling pathway components. This study also classified that molecules might serve as molecular targets for the treatment of pathological skin conditions such as chronic wounds and excessive scarring (fibrosis).
			Exogenously added TGF-β has the potential to promote wound healing by stimulating angiogenesis, immune cell infiltration, and ECM production, and that diminishing endogenous TGF-β action reduces scarring without adversely affecting wound-healing quality.

			Interpreting wound-healing results obtained from the animals brought about its limitations. For instance, an underlying skin abnormality was found on many of the mouse models with genetic alterations in the TGF-β signalling pathway. Also, the pleiotropic effects of TGF-β on many different cell types throughout stages of wound healing highlighted a challenge in designing particular methods in which the TGF-β signalling pathway can assist wound healing or reduce scarring. <ref><pubmed>24761336</pubmed></ref>

	Exogenously added TGF-β has the potential to promote wound healing by stimulating angiogenesis, immune cell infiltration, and ECM production, and that diminishing endogenous TGF-β action reduces scarring without adversely affecting wound-healing quality.		====Direct modulation of TGF-β levels====
	===Direct modulation of TGF-β levels===
	Injecting TGF-β into normal skin of newborn mice led to resilient initiation of angiogenesis and fibrosis. This consisted of important new collagen synthesis combined into the matrix. As a result of these observations, people were encouraged to further study the administration of TGF-β to incisional wounds in rats. It proved that TGF-β treatment resulted in better dermal healing, as showed by prominent collagen deposition and significantly increased wound strength.<ref><pubmed>24761336</pubmed></ref>		Injecting TGF-β into normal skin of newborn mice led to resilient initiation of angiogenesis and fibrosis. This consisted of important new collagen synthesis combined into the matrix. As a result of these observations, people were encouraged to further study the administration of TGF-β to incisional wounds in rats. It proved that TGF-β treatment resulted in better dermal healing, as showed by prominent collagen deposition and significantly increased wound strength.<ref><pubmed>24761336</pubmed></ref>

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	Out of the number of TGF-β1 null (knockout) mice that are generated in the laboratory, it is estimated that around 60% die in utero and the 40% that survive develops normally to term. During the first 2 weeks of postnatal life, the mice appear normal and look healthy. However, after 3 to 4 weeks, they start to develop a rapid wasting syndrome, which is largely characterised by a great decrease in bodt weight gain in contrast with controls. At this point, the mice become inactive and appear sick with unhealthy looking fur. Some can survive up to 4 or 5 weeks. The healthy animals are separated from their mother as the mother has the responsibility to care for the sick animals. Surprisingly, it is the affected animals that have a longer life span.		Out of the number of TGF-β1 null (knockout) mice that are generated in the laboratory, it is estimated that around 60% die in utero and the 40% that survive develops normally to term. During the first 2 weeks of postnatal life, the mice appear normal and look healthy. However, after 3 to 4 weeks, they start to develop a rapid wasting syndrome, which is largely characterised by a great decrease in bodt weight gain in contrast with controls. At this point, the mice become inactive and appear sick with unhealthy looking fur. Some can survive up to 4 or 5 weeks. The healthy animals are separated from their mother as the mother has the responsibility to care for the sick animals. Surprisingly, it is the affected animals that have a longer life span.

	[[File:Graph depicting the body weight of TGF-β1 knockout mice compared to normal mice.png\|thumb\|~~500px~~\|Graph depicting the body weight of TGF-β1 knockout mice compared to normal mice as a function of time<ref><pubmed>7856732</pubmed></ref>]]		[[File:Graph depicting the body weight of TGF-β1 knockout mice compared to normal mice.png\|600px\|thumb\|left\|Graph depicting the body weight of TGF-β1 knockout mice compared to normal mice as a function of time<ref><pubmed>7856732</pubmed></ref>]]

	All of the knockout mice have a multifocal inflammatory disease in many tissues. The heart and lungs were the organs that were affected to the greatest degree, following the stomach, colon and pancreas.		All of the knockout mice have a multifocal inflammatory disease in many tissues. The heart and lungs were the organs that were affected to the greatest degree, following the stomach, colon and pancreas.
	No lesions in the TGF-B1 knockout mice were found in the animals that died during the first week of life. The earliest lesion was seen at 8 days of age in the lung and heart.		No lesions in the TGF-B1 knockout mice were found in the animals that died during the first week of life. The earliest lesion was seen at 8 days of age in the lung and heart.
	REWORD
	Increased adhesion of leukocytes to the endothelium of pulmonary veins is the inital lesion seen at day 8 postnatally and is soon followed by perivascular cuffing as well as inflammatory infiltrates in lung parenchyma. The lesions in the heart begin as endocarditis and then progress to myocarditis and pericarditis. Within the lung, chronic inflammatory infiltrates consist of T and B lymphocytes, including plasma cells, whereas macrophages are the primary inflammatory cell type in the heart. Increased expression of major histocompatibility complex class I and II proteins is seen in pulmonary vascular endothelium as early as day 8. An immunoblastic response in mediastinal and mandibular lymph nodes and spleen is also seen. In the absence of any pathogens, this massive inflammatory disease, together with overexpression of major histocompatibility complex class I and II proteins and overproduction of immunoglobulins by lymphocytes, offers circumstantial evidence for an autoimmune etiology.
			REWORD Increased adhesion of leukocytes to the endothelium of pulmonary veins is the inital lesion seen at day 8 postnatally and is soon followed by perivascular cuffing as well as inflammatory infiltrates in lung parenchyma. The lesions in the heart begin as endocarditis and then progress to myocarditis and pericarditis. Within the lung, chronic inflammatory infiltrates consist of T and B lymphocytes, including plasma cells, whereas macrophages are the primary inflammatory cell type in the heart. Increased expression of major histocompatibility complex class I and II proteins is seen in pulmonary vascular endothelium as early as day 8. An immunoblastic response in mediastinal and mandibular lymph nodes and spleen is also seen. In the absence of any pathogens, this massive inflammatory disease, together with overexpression of major histocompatibility complex class I and II proteins and overproduction of immunoglobulins by lymphocytes, offers circumstantial evidence for an autoimmune etiology.

	<ref><pubmed>7856732</pubmed></ref>		<ref><pubmed>7856732</pubmed></ref>

	Interpreting wound-healing results obtained from the animals brought about its limitations. For instance, an underlying skin abnormality was found on many of the mouse models with genetic alterations in the TGF-β signalling pathway. Also, the pleiotropic effects of TGF-β on many different cell types throughout stages of wound healing highlighted a challenge in designing particular methods in which the TGF-β signalling pathway can assist wound healing or reduce scarring. <ref><pubmed>24761336</pubmed></ref>

	==Current Research==		==Current Research==

← Older revision		Revision as of 10:05, 7 August 2018
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	TGF-βRII binding enables dimerization with TGF-β type I receptor (TGF-βRI) homodimers, as well as activation of the TGF-βRI kinase domain and signal transduction across phosphorylation of the C-terminus of receptor-regulated SMADs, SMAD2 and SMAD3.		TGF-βRII binding enables dimerization with TGF-β type I receptor (TGF-βRI) homodimers, as well as activation of the TGF-βRI kinase domain and signal transduction across phosphorylation of the C-terminus of receptor-regulated SMADs, SMAD2 and SMAD3.
	A heterotrimeric complex is formed by the TGF-βR dimer and SMAD4, which moves and assemblies in the nucleus.		A heterotrimeric complex is formed by the TGF-βR dimer and SMAD4, which moves and assemblies in the nucleus.
	TGF-β dependent signalling can operate or subdue numerous target genes through the communication of SMADs with multiple transcription factors. There are many structures in which SMAD activities are regulated, such as SMAD2/3 nucleocytoplasmic shuttling, binding to anchor proteins, phosphorylation and Smurf (SMAD-ubiquitination-regulatory factor). ~~<ref><pubmed>~~24393789 ~~</pubmed></ref>~~		TGF-β dependent signalling can operate or subdue numerous target genes through the communication of SMADs with multiple transcription factors. There are many structures in which SMAD activities are regulated, such as SMAD2/3 nucleocytoplasmic shuttling, binding to anchor proteins, phosphorylation and Smurf (SMAD-ubiquitination-regulatory factor). {{#pmid:24393789\|PMID24393789}}

	===Non-Canonical pathway===		===Non-Canonical pathway===
	In the non-canonical pathway, SMAD-independent pathways such as PI3K/AKT and MAPK pathways like ERK, JNK, and p38 MAPK are activated by TGF-β signalling. In addition, transversal signalling, especially at the SMAD level, allows TGF-β pathway activation to incorporate signals from integrins, Notch and Wnt dependent pathways as well as signals from cellular processes like the cell cycle or apoptosis machineries. Thus, the TGF-β signalling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, cell motility, extracellular matrix production, angiogenesis and cellular immune response.~~<ref><pubmed>~~24393789 ~~</pubmed></ref>~~		In the non-canonical pathway, SMAD-independent pathways such as PI3K/AKT and MAPK pathways like ERK, JNK, and p38 MAPK are activated by TGF-β signalling. In addition, transversal signalling, especially at the SMAD level, allows TGF-β pathway activation to incorporate signals from integrins, Notch and Wnt dependent pathways as well as signals from cellular processes like the cell cycle or apoptosis machineries. Thus, the TGF-β signalling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, cell motility, extracellular matrix production, angiogenesis and cellular immune response.{{#pmid:24393789\|PMID24393789}}

	==Process of TGF-β signalling pathway==		==Process of TGF-β signalling pathway==
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	===SMAD Dependent TGF-β signalling pathway===		===SMAD Dependent TGF-β signalling pathway===

	[[File:TGF-B Signalling - Formation of Receptor Hetero-Tetramers.png\|thumb\|350px\|SMAD Dependent TGF-β signalling pathway: Formation of Receptor Hetero-Tetramers~~<ref><pubmed>~~16446785~~</pubmed></ref>~~]]		[[File:TGF-B Signalling - Formation of Receptor Hetero-Tetramers.png\|thumb\|350px\|SMAD Dependent TGF-β signalling pathway: Formation of Receptor Hetero-Tetramers{{#pmid:16446785\|PMID16446785}}]]

	The ligands of the TGF-β superfamily form dimers that bind to heterodimeric receptor complexes composed of two type I and two type II transmembrane receptor subunits with serine/threonine kinase domains.		The ligands of the TGF-β superfamily form dimers that bind to heterodimeric receptor complexes composed of two type I and two type II transmembrane receptor subunits with serine/threonine kinase domains.
	Following ligand binding on TGF-β1, the dimerized TGF-β type II receptors phosphorylates and activates the TGF-β type I receptors. In most cell types, this leads to recruitment and phosphorylation of the receptor-regulated SMAD2 and SMAD3, presented by the SMAD anchor for receptor activation. SMAD1 and SMAD5 can be activated by the TGF-β signaling depending on the Type I receptor that is expressed.		Following ligand binding on TGF-β1, the dimerized TGF-β type II receptors phosphorylates and activates the TGF-β type I receptors. In most cell types, this leads to recruitment and phosphorylation of the receptor-regulated SMAD2 and SMAD3, presented by the SMAD anchor for receptor activation. SMAD1 and SMAD5 can be activated by the TGF-β signaling depending on the Type I receptor that is expressed.
	Heterologous complexes are formed by the phosphorylated receptor-regulated SMAD with the common-mediator SMAD, SMAD4, and successively move into the nucleus, where they accumulate and act as transcription factors participating in the regulation of target gene expression. ~~<ref><pubmed>~~21302608~~</pubmed></ref>~~		Heterologous complexes are formed by the phosphorylated receptor-regulated SMAD with the common-mediator SMAD, SMAD4, and successively move into the nucleus, where they accumulate and act as transcription factors participating in the regulation of target gene expression.{{#pmid:21302608\|PMID21302608}}
	In addition, they recruit extra transcriptional regulators, such as DNA-binding transcription factors, co-activators and co-repressors. These control the expression of several target genes and ultimately initiates a SMAD-dependent signaling cascade that induces or represses transcriptional activity. SMADs are widely expressed in most adult tissue and cell types, indicating that the TGF-β signaling pathway is ubiquitous.		In addition, they recruit extra transcriptional regulators, such as DNA-binding transcription factors, co-activators and co-repressors. These control the expression of several target genes and ultimately initiates a SMAD-dependent signaling cascade that induces or represses transcriptional activity. SMADs are widely expressed in most adult tissue and cell types, indicating that the TGF-β signaling pathway is ubiquitous.

	===SMAD independent TGF-β signalling pathway===		===SMAD independent TGF-β signalling pathway===

	Rather than SMAD-mediated transciption TGF-β also has the potential to activate other signalling cascades for example the Erk, JNK and p38 MAPK kinase pathways. In some cases these pathways exhibit activation with slow kinetics which indicates SMAD-dependant mechanics, however there has also been rapid activation cases (5-15mins) suggesting independence from transcription mechanisms. Studies carried out with SMAD4 deficient cells and dominant-negative SMADS provide evidence that the MAPK pathway activation is independent from SMADS, as well as this it has be found that p38 MAPK signalling was activated in response to mutated TGF- β type 1 receptors, which were defective in SMAD activation~~<ref name="~~PMID14534577~~"><pubmed>14534577</pubmed></ref>~~.		Rather than SMAD-mediated transciption TGF-β also has the potential to activate other signalling cascades for example the Erk, JNK and p38 MAPK kinase pathways. In some cases these pathways exhibit activation with slow kinetics which indicates SMAD-dependant mechanics, however there has also been rapid activation cases (5-15mins) suggesting independence from transcription mechanisms. Studies carried out with SMAD4 deficient cells and dominant-negative SMADS provide evidence that the MAPK pathway activation is independent from SMADS, as well as this it has be found that p38 MAPK signalling was activated in response to mutated TGF- β type 1 receptors, which were defective in SMAD activation{{#pmid:14534577\|PMID14534577}}.

	The precise mechanisms and biological consequences of these SMAD-Independent pathways (Erk, JNK, p38 MAPK) are currently poorly characterized. Ras is implicated in TGF- β induced Erk signalling as there is rapid activation of Ras by TGF- β in epithelial cells. The JNK and p38 MAPK signalling are activated by various MAPK kinase kinases (MAPKKK) TGF- β kinase 1 (TAK 1) receptor is a MAPKKK family member. Further research and identification of various interactions between the small signalling molecules and receptor proteins will provide additional insight into the precise mechanism behind the activation of MAPK pathways by TGF- β ligands <ref name="PMID14534577"/>.		The precise mechanisms and biological consequences of these SMAD-Independent pathways (Erk, JNK, p38 MAPK) are currently poorly characterized. Ras is implicated in TGF- β induced Erk signalling as there is rapid activation of Ras by TGF- β in epithelial cells. The JNK and p38 MAPK signalling are activated by various MAPK kinase kinases (MAPKKK) TGF- β kinase 1 (TAK 1) receptor is a MAPKKK family member. Further research and identification of various interactions between the small signalling molecules and receptor proteins will provide additional insight into the precise mechanism behind the activation of MAPK pathways by TGF- β ligands <ref name="PMID14534577"/>.
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	==Regulation of the pathway and factors affecting it==		==Regulation of the pathway and factors affecting it==

	Signalling mechanisms by TGF-β like factors are regulated in both negative and positive fashions, these are all tightly controlled through a multitude of mechanisms at extracellular, membrane, cytoplasmic and all the way to nuclear levels. Positive regulation is required to amplify signalling from TGF-β like factors, while negative regulation is important for the termination and restriction of signalling usually occurring through the mechanism of a feedback loop. There is also additional regulation of TGF-β like factors via cross-talk with other signal transduction pathways such as MAPK and JAK/STAT pathways.~~<ref name="~~PMID10704361~~"><pubmed>10704361</pubmed></ref>~~		Signalling mechanisms by TGF-β like factors are regulated in both negative and positive fashions, these are all tightly controlled through a multitude of mechanisms at extracellular, membrane, cytoplasmic and all the way to nuclear levels. Positive regulation is required to amplify signalling from TGF-β like factors, while negative regulation is important for the termination and restriction of signalling usually occurring through the mechanism of a feedback loop. There is also additional regulation of TGF-β like factors via cross-talk with other signal transduction pathways such as MAPK and JAK/STAT pathways.{{#pmid:10704361\|PMID10704361}}

	===Positive Regulation===		===Positive Regulation===
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	TGF betas are involved in embryogenesis. During development of the embryo, members of the TGF-beta family are essential for bone and cartilage formation, mesoderm induction and patterning and dorso-ventral patterning.		TGF betas are involved in embryogenesis. During development of the embryo, members of the TGF-beta family are essential for bone and cartilage formation, mesoderm induction and patterning and dorso-ventral patterning.

	[[File:TGF in Cardiovascular.jpg\|thumb\|500px\|Expression of TGF-β2 and TGF-β3 in wildtype embryonic hearts.~~<ref><pubmed>~~12948523~~</pubmed></ref>~~]]		[[File:TGF in Cardiovascular.jpg\|thumb\|500px\|Expression of TGF-β2 and TGF-β3 in wildtype embryonic hearts.{{#pmid:12948523\|PMID12948523]]
	===Cardiovascular Development===		===Cardiovascular Development===

	Genetic engineering and tissue explanation studies have revealed many roles for TGF-β ligands and their signaling molecules in development. In the embryo, TGF-β appear to be involved in epithelial-mesenchymal transformations (EMT) during the formation of endocardial cushions, and in epicardial epithelial-mesenchymal transformations essential for coronary vasculature, ventricular myocardial development and compaction. It must be noted that in the normal function of the cardiovascular system in the adult, TGF-β play significant roles in cardiac hypertrophy, vascular remodeling and regulation of the renal renin-angiotensin system.		Genetic engineering and tissue explanation studies have revealed many roles for TGF-β ligands and their signaling molecules in development. In the embryo, TGF-β appear to be involved in epithelial-mesenchymal transformations (EMT) during the formation of endocardial cushions, and in epicardial epithelial-mesenchymal transformations essential for coronary vasculature, ventricular myocardial development and compaction. It must be noted that in the normal function of the cardiovascular system in the adult, TGF-β play significant roles in cardiac hypertrophy, vascular remodeling and regulation of the renal renin-angiotensin system.

	TGF-β1 is expressed in the endocardium of the developing mouse. TGF-β(-/-) mice have been found with obvious congenital cardiovascular defects, so it’s important to review its expression in the developing heart. In the blood vessels, TGF-β1 is in the intima whereas TGF-β2 and TGF-β3 are in the media and adventitia. TGF-β2 signals are found as early as embryonic day 7.25 (E7.25) ~~<ref><pubmed>~~7687212~~</pubmed></ref>~~ in the cardiogenic plate of the precardiac mesoderm and is later prominent in the myocardium of the aortic sac and outflow track regions. TGF-β2 protein is also found in the entire myocardium of the heart at the time when looping occurs. From E8.5-9.5 when the cushion formation process occurs, there is a particularly strong TGF-β2 expression localised to the myocardium as displayed in A, B, D and E in the figure. After cushion formation and EMT, and before myocardialization of the endocardial cushion begins, there is also strong TGF-β2 expression in the OT myocardium and in the adjacent developing cushion mesenchym. However, as myocardialization occurs, TGF-β2 expression is reduced in the myocardium so that from E12.5 onwards, it is only expressed mainly in the mesenchyme of the cushion and OT septum. As can be seen in 2GH, TGF-β2 expression remains high in the cushion mesenchyme of the OT septum. By E15.5, TGF-β1 s now the most highly expressed isoform in the endocardial cells of the myocardium. It is seen in M, N, O of the figure that the epidcardium TGF-β1 and TGF-β3 expression is higher than that of TGF-β2. Thus, it can be seen that all three TGF-β are expressed in the epicardium, and they are not expressed in an overlapping fashion.		TGF-β1 is expressed in the endocardium of the developing mouse. TGF-β(-/-) mice have been found with obvious congenital cardiovascular defects, so it’s important to review its expression in the developing heart. In the blood vessels, TGF-β1 is in the intima whereas TGF-β2 and TGF-β3 are in the media and adventitia. TGF-β2 signals are found as early as embryonic day 7.25 (E7.25){{#pmid:7687212\|PMID7687212}} in the cardiogenic plate of the precardiac mesoderm and is later prominent in the myocardium of the aortic sac and outflow track regions. TGF-β2 protein is also found in the entire myocardium of the heart at the time when looping occurs. From E8.5-9.5 when the cushion formation process occurs, there is a particularly strong TGF-β2 expression localised to the myocardium as displayed in A, B, D and E in the figure. After cushion formation and EMT, and before myocardialization of the endocardial cushion begins, there is also strong TGF-β2 expression in the OT myocardium and in the adjacent developing cushion mesenchym. However, as myocardialization occurs, TGF-β2 expression is reduced in the myocardium so that from E12.5 onwards, it is only expressed mainly in the mesenchyme of the cushion and OT septum. As can be seen in 2GH, TGF-β2 expression remains high in the cushion mesenchyme of the OT septum. By E15.5, TGF-β1 s now the most highly expressed isoform in the endocardial cells of the myocardium. It is seen in M, N, O of the figure that the epidcardium TGF-β1 and TGF-β3 expression is higher than that of TGF-β2. Thus, it can be seen that all three TGF-β are expressed in the epicardium, and they are not expressed in an overlapping fashion.

	Cross talk between mesoderm and underlying endoderm is needed to form the early tubular heart. This cellular and molecular induction in the primary heart forming regions is important for the specification and differentiation of myocardial and endocardial precursor cells ~~<ref><pubmed>~~10767078~~</pubmed></ref>~~. Other endoderm-derived growth factors such as BMP2, FGF2 as well as TGFBS have been implicated in this process in the avian system ~~<ref><pubmed>~~11322300~~</pubmed></ref>~~. TGFB2 and TGFB receptors are expressed in the precardiac mesoderm along with BMP2 ~~<ref><pubmed>~~7687212~~</pubmed></ref>~~<ref><pubmed>10767078</pubmed></ref><ref><pubmed>10340759</pubmed></ref>. Members of the TGG family can serve as inductive signals at the heart forming fields for the formation of myocardial and endocardial precursor cells. Members such as Activin, BMP, Nodal, Left and others have been found to be crucial for the establishment of embryonic asymmetry <ref><pubmed>11836504</pubmed></ref>, and this asymmetry is in turn critical for heart development <ref><pubmed>11752633</pubmed></ref>.		Cross talk between mesoderm and underlying endoderm is needed to form the early tubular heart. This cellular and molecular induction in the primary heart forming regions is important for the specification and differentiation of myocardial and endocardial precursor cells{{#pmid:10767078\|PMID10767078}}. Other endoderm-derived growth factors such as BMP2, FGF2 as well as TGFBS have been implicated in this process in the avian system{{#pmid:11322300\|PMID11322300}}. TGFB2 and TGFB receptors are expressed in the precardiac mesoderm along with BMP2{{#pmid:7687212\|PMID7687212}}<ref><pubmed>10767078</pubmed></ref><ref><pubmed>10340759</pubmed></ref>. Members of the TGG family can serve as inductive signals at the heart forming fields for the formation of myocardial and endocardial precursor cells. Members such as Activin, BMP, Nodal, Left and others have been found to be crucial for the establishment of embryonic asymmetry <ref><pubmed>11836504</pubmed></ref>, and this asymmetry is in turn critical for heart development <ref><pubmed>11752633</pubmed></ref>.


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	<references/>		<references/>

			{{student image}}

	[[Category:TGF-beta]]		[[Category:TGF-beta]]