2016 Group Project 3

2016 Student Projects
Signalling: 1 Wnt | 2 Notch | 3 FGF Receptor | 4 Hedgehog | 5 T-box | 6 TGF-Beta
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Fibroblast Growth Factor Receptor (FGFR) Pathway

Introduction

The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.)

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

History

Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article.

Year	Scientific Discovery Regarding FGF/FGFR Signalling
1939	The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
1974	FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
1987	The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
1989	FGF1 and FGF2 were isolated from brain tissue.
1990	FGFR tyrosine kinases were identified for the first time
1991	FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
2005	A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
2013	A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.

Overview Of The FGFR Pathway

23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14).

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction.

Simplistic illustration of the FGFR receptors adapted from review article Functions and regulations of fibroblast growth factor signaling during embryonic development

Subtypes of FGFR

FGFR Subtype	Function	Abnormalities
FGFR1	Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation Involved in formation of the organ of corti and auditory sensory epithelium Expressed in early limb bud Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes Is a negative regulator of bone growth	Pfeiffer Syndrome (Type 1) Kallmann syndrome Osteoglophonic dysplasia 8p11 myeloproliferative syndrome
FGFR2	Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates Acts as a marker of prechondrogenic condensations Expressed in condensing mesenchyme of the early limb bud Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts Is involved in cranial cell replication or differentiation in both humans and mice.	Pfeiffer Syndrome (Type 1-3) Apert Syndrome Crouzon Syndrome Beare-Stevenson cutis gryata syndrome
FGFR3	Induces complete growth arrest of cells Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed	Achondroplasia (can be severe, with developmental delay and acanthuses) Thanatophoric Dysplasia Hypochondroplasia
FGFR4	Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis It will provide mitogenic and morphogenic signals to regulate normal limb development Promotes intramembranous ossification and participates in the development of calvarial bone	Chondrodysplasia

Signal Transduction

FGFR Signalling Pathway (Image based upon)

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) .

In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses .

With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis .

YouTube video outlining FGF Signalling Pathway
<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media> This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.

Signal Transduction

FGFR Signalling Pathway (Image based upon)

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) .

In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses .

With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis .

YouTube video outlining FGF Signalling Pathway
<html5media height="400" width="533">https://www.youtube.com/watch?v=DUBelRjjqvc</html5media> This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.