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. 2021 May 10;10(5):1154. doi: 10.3390/cells10051154

Figure 1.

Figure 1

Simplified overview of FGFR canonical signalling pathways. FGFs bind to FGFR inducing receptor dimerisation which then drives the transphosphorylation of the tyrosine kinase domain in the intracellular compartment of the cell. The intracellular portion of active FGFR is phosphorylated at multiple tyrosine sites. In the C-terminus, tyrosine phosphorylation acts as a docking site for molecules containing SH2 domains such as PLCγ. Phosphorylation of PLCγ hydrolyses PIP2 to produce DAG and IP3, inducing the release of calcium cations and subsequent activation of PKC. In the intracellular juxtamembrane region of FGFR, phosphorylation leads to the recruitment of FRS2 which then acts as a secondary docking protein to form two independent complexes. One complex is FRS2-GRB2-SOS that activates RAS, which in turn activates the MAPK pathway. A second complex is FRS2-GRB2-GAB1, which drives the activation of PI3K/AKT pathway. Other pathways are also known to be activated by FGFR such as STAT, p38 MAPK, JNK, SRC and RSK2 pathways. Collectively, these pathways play multiple roles in cell survival, growth, migration, differentiation and metabolism. FGFR signalling is regulated by receptor internalisation upon ubiquitination by CBL or by negative modulation by different proteins (shown in bold red) such as MKP, SEF and SPRY. The yellow stars represent tyrosine phosphorylation sites. HS: heparin sulphate; FRS2: FGFR substrate 2; PLCγ: protein phospholipase Cγ; PIP2: phosphatidylinositol 4,5-bisphosphate; DAG: diacylglycerol; IP3: IP3 inositol 1,4,5-triphosphate; Ca2+: calcium; PKC: protein kinase C; GRB2: growth factor receptor-bond 2; SOS: son of sevenless; MAPK: mitogen-activated protein kinase; PI3K: phosphoinositide 3-kinase; MEK: intracellular mitogen-activated protein kinase/Erk kinase; RAF: Raf-1 proto-oncogene, serine/threonine kinase; RAS: proto-oncogene GTPase; GAB1: GRB2-associated binding protein 1; AKT: Akt serine/threonine kinase 1; JAK: janus kinase; STAT: signal transducer and activator of transcription; CBL: Cbl proto-oncogene E3 ubiquitin protein ligase; MKP: MAPK phosphatases; SEF: similar expression to fgf genes; SPRY: sprouty homolog.