Development - FGFR signaling pathway

FGFR signaling pathway

Fibroblast growth factor 2 (FGF2) has been implicated in diverse cellular processes, including apoptosis, cell survival, chemotaxis, cell adhesion, migration, differentiation, and proliferation [1].

FGF2 induces biological responses by binding to and activating Fibroblast growth factor receptor 1 (FGFR1), a subfamily of cell surface receptor tyrosine kinases (RTKs). FGFR1 interacts with components of the extracellular matrix, in particular heparan sulfate proteoglycans (such as Perlecan). Perlecan protects the FGF2 from thermal denaturation and proteolysis, and is required for activation of the FGFR1 and for defining the mode of interaction between specific FGF-FGFR pairs. Heparin binds directly to FGF2 and FGFR1 and thereby modulates activation of the FGFR1 [2].

Transmembrane heparan sulfate proteoglycans (Syndecan-1, Syndecan-2 and Syndecan-4) are able to bind FGF2 to heparan sulfate chains and present it to the FGFR1. Remodeling of heparan sulfate chains may affect FGF2 signaling [3], [4].

The most common pathway employed by FGF2 is the mitogen-activated protein kinase (MAPK) pathway. The process involves the lipid-anchored docking protein Fibroblast growth factor receptor substrate 2 (FRS2) that constitutively binds FGFR1 even when the receptor is not activated. FGFR1 can phosphorylate FRS2 and Src homology 2 domain containing transforming protein (Shc). Phosphorylated FRS2 binds the adapter protein Growth factor receptor bound 2 (GRB2) and the Protein tyrosine phosphatase, non-receptor type 11 (SHP-2). In FGFR1/ FRS2 signaling pathway, SHP-2 acts as adapter protein. Shc and GRB2 form a complex with the Guanine nucleotide exchange factor Son of sevenless proteins (SOS). Translocation of this complex to the plasma membrane by binding to phosphorylated FRS2 allows SOS to activate v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) by GTP exchange due to its close proximity to membrane-bound H-Ras. Once in the active GTP-bound state, H-Ras interacts with several effector proteins, including v-Raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1). That results in activation of the Mitogen-activated protein kinase kinases 1 and 2 (MEK1/2)/ Mitogen-activated protein kinases 1 and 3 (ERK1/2) signaling cascade. This cascade leads to phosphorylation of the target transcription factor ELK1 [5], [6], [7], [8].

GRB2 is bound to tyrosine-phosphorylated FRS2, and the C-terminal SH3 domain of GRB2 forms a complex with the proline-rich region of GRB2-associated binding protein 1 (GAB1) to serve as an interface between these two docking proteins. Phosphatidylinositol-3-kinase kinase (PI3K) is one of the effectors of GAB1 and thus might be involved in FGF-induced activation of PI3K [9].

Assembly of FRS2/ GRB2/ GAB1 complex induced by FGF stimulation leads to activation of the PI3K and the downstream effector proteins such as the v-AKT murine thymoma viral oncogene homolog (AKT) which cellular localization and activity is regulated by product of PI3K, Phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) [10].

Cas-Br-M ecotropic retroviral transforming sequence (c-Cbl) is a regulator that functions as the ubiquitin ligase. It ubiquitinates and promotes the degradation of a variety of cell signaling proteins. c-Cbl is recruited by GRB2 to the FRS2 multiprotein complex in response to the FGF2 stimulation, resulting in ubiquitination of FRS2 and FGFR1 [11].

FGF2 activates stress-activated protein kinase/c-Jun N-terminal kinase (JNK(MAPK8-10)) and the transcription factor c-Jun. The adaptor protein CRK is tyrosine-phosphorylated by FGFR1. Formation of this stable complex between the CRK and FGFR1 is dependent on phosphorylated state of the receptor. Interaction between CRK and guanine nucleotide exchange factor DOCK1 induces the Ras-related C3 botulinum toxin substrate 1 (Rac1) activation and its translocation to the membrane. Activated Rac1 stimulates the cascade that involves p21-Activated kinase 1 (PAK1)/ Mitogen-activated protein kinase kinase kinase 1 (MEKK1)/ Dual specificity Mitogen-activated protein kinase kinase 4 (MEK4)/ JNK(MAPK8-10) by a Ras-independent mechanism [12].

FGF2 mediates activation of p38 MAPK via adaptor proteins Src homology 2 domain containing adaptor protein B (SHB), Epidermal growth factor receptor pathway substrate 8 (EPS8) and Abl-interactor 1 (E3b1(ABI-1)). EPS8 and E3b1(ABI-1) participate in the transduction of signals to Rac1, by regulating Rac-specific activities of the guanine nucleotide exchange factors (GEF). EPS8, E3b1(ABI-1) and SOS form a trimeric complex that exhibits Rac-specific GEF activity. Rac1 activates Mitogen-activated protein kinase kinase kinase 11 (MLK3(MAP3K11)), Mitogen-activated protein kinase kinase 6 (MEK6(MAP2K6)), and p38 MAPK and its downstream target MAPK-activated protein kinase-2 (MAPKAPK-2). That ultimately leads to transcriptional activation of the cyclic AMP response element-binding protein (CREB1) and activation of the transcription factor ATF-2 [13], [14].

FGF2 plays a critical role in the hydrolysis of membrane phospholipids in cells. Upon binding to FGFR1, FGF2 stimulates cytosolic form of Phospholipase C-gamma1 (PLC-gamma 1) that in turn hydrolyzes Phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2) to Diacylglycerol (DAG) and Inositol trisphosphate (IP3). DAG and IP3 are second messengers. IP3 activates IP3 receptor and induces the release of Ca('2+) from intracellular Ca('2+) storage and accumulation of Ca('2+) in the cytoplasm. DAG activates Protein kinase C delta (PKC-delta) [15].

Fibroblast growth factor 2 (FGF2) is a known inducer of epithelial-to-mesenchymal transition (EMT). FGF2 induces EMT via PI3K [16], [17], [18].

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