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 .
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
Heparin binds directly to FGF2
and FGFR1 and thereby modulates activation of the
Transmembrane heparan sulfate proteoglycans
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 , .
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
, , , .
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 .
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
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
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 .
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 , .
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
Fibroblast growth factor 2 (FGF2) is a known inducer of
epithelial-to-mesenchymal transition (EMT). FGF2 induces EMT
via PI3K , , .
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