EGFR signaling pathway
Epidermal growth factor receptor (EGFR) belongs to the
ERBB family of receptor tyrosine kinases that contains four
closely related members EGFR and ERBB2-4. They couple the
binding of the extracellular growth factor ligands to intracellular signaling pathways
that regulate diverse biologic responses, including proliferation, differentiation, cell
motility, and survival .
Six ligands of EGFR are known. These are Epidermal growth
factor (EGF), Amphiregulin,
Transforming growth factor alpha (TGF-alpha),
Betacellulin, Heparin binding EGF-like growth factor
(HB-EGF), and Epiregulin .
ErbB2 is a unique member of the ERBB family in that it
does not bind any of the known ligands with high affinity. However, it is the preferred
heterodimeric partner for other EGFRs .
The ligand-induced receptor dimerization and subsequent autophosphorylation of
distinct tyrosine residues creates docking sites for various membrane-targeted proteins.
The cytoplasmic mediators that bind to EGFR phosphotyrosine
residues are either the adaptor proteins, such as SHC transforming protein 1
(Shc), Growth factor
receptor-bound protein 2 (GRB2),
Cas-Br-M ecotropic retroviral transforming sequence
(c-Cbl), Docking protein 2
(DOK2) and NCK adaptor protein 1
(NCK1), or enzymes, such as
Phospholipase C gamma 1 (PLC-gamma 1), v-Src sarcoma viral
oncogene homolog (c-Src) and PTK2 protein tyrosine kinase 2
The adaptors Shc and GRB2
recruit the exchange factor Son of sevenless homolog 1
(SOS) and form the complex consisting of
Shc, GRB2 and
SOS. Activated SOS activates
small GTPase v-Ha-ras Harvey rat sarcoma viral oncogene homolog
(H-Ras) by its conversion from the inactive
GDP-bounding state to the active GTP-bounding state. The activated H-Ras
stimulates v-Raf-1 murine leukemia viral oncogene homolog 1
(c-Raf-1) / Mitogen-activated protein kinase kinase 1 and 2
(MEK1 and MEK2)/ Mitogen-activated protein kinase 1 and 3
(ERK1/2) kinase cascade that leads to activation of the
transcription factors ELK1 member of ETS oncogene family
(Elk-1), v-Myc myelocytomatosis viral oncogene homolog
(c-Myc), and v-Fos FBJ murine osteosarcoma viral oncogene
homolog (c-Fos) .
The adaptor DOK2 associates with the GTPase-activating
protein RAS p21 protein activator 1 (p120GAP) that
reinforces intrinsic GTPase activity of H-Ras, thereby
inactivating H-Ras. As a result, DOK2
can attenuate activation of the EGF-stimulated mitogen-activated protein
kinase (MAPK) cascade .
The adaptor NCK1 couples
EGFR stimulation to the activation of another MAPK-cascade,
the JNK kinase cascade. NCK1 recruits p21-Activated kinase 1
PAK1 complex binds Mitogen-activated protein kinase kinase
kinase 10 (MLK2) and activates the JNK cascade consisting of
MLK2/ Mitogen-activated protein kinase kinase 4 and 7
(MEK4 and MKK7)
/ Mitogen-activated protein kinase 8 and 9
(JNK1 and JNK2). The
recruitment of the cascade to the activated membrane receptor localizes
MLK2 on the plasma membrane where it is activated by its
known upstream effectors, such as Ras-related C3 botulinum toxin substrate 1
(Rac1). Stimulation of JNK cascade results in activation of
the transcription factors Elk-1, Jun oncogene
(c-Jun) and some
others . Dual specificity phosphatases 1 and
4 (MKP-1 and MKP-2) attenuate
activation of the JNK cascade .
The adaptor GRB2 also binds via its SH3 domain with
proline-rich regions of the c-Cbl protein.
c-Cbl is tyrosine-phosphorylated by tyrosine kinase upon
stimulation via the EGF receptor. EGF stimulation induces the association of
c-Cbl with the regulatory p85 subunit of the
Phosphatidylinositol 3-kinase (PI3K reg class IA (p85))
Activated PI3K cat class IA converts Phosphatidylinositol
4,5-biphosphate (PtdIns(4,5)P2) to Phosphatidylinositol 3,4,5-triphosphate
(PtdIns(3,4,5)P3). The latter is a second messenger involved
in regulation of various processes . PtdIns(3,4,5)P3
associates with the inner surface of the plasma membrane and promotes the
recruitment of proteins with pleckstrin homology (PH) domains. One of such proteins is
serine/threonine kinase v-AKT murine thymoma viral oncogene homolog
(AKT). It is the essential mediator of various cell
processes, such as apoptosis, cell cycle, protein synthesis, regulation of metabolism
Enzymes such as PLC-gamma 1 or the cytoplasmic tyrosine
kinase c-Src tie EGFR
activation to the generation of secondary messengers and calcium metabolism or to
mitogenic signaling cascades, respectively. EGFR recruits
and phosphorylates PLC-gamma 1 .
Phosphorylated PLC-gamma 1 generates Diacylglycerol
(DAG) and Inositol-1,4,5-trisphosphate
(IP3) from PtdIns(4,5)P2 .
DAG activates many isoforms of Protein kinase C
(PKC), including conventional isoforms alpha, beta, and
gamma (PKC-alpha, PKC-beta, and PKC-gamma), as well as
PKC-epsilon and PKC-theta.
PKC-alpha, PKC-beta, PKC-gamma, and
PKC-epsilon phosphorylate and activate
c-Raf-1, thereby amplifying
H-Ras/ MEK1 and
MEK2/ ERK1/2 kinase cascade
, . PKC-theta
activates Nuclear factor NF-kappa-B inhibitor kinase beta
(IKK-beta) resulting in
activation of the Nuclear factor NF-kappa-B (NF-kB) .
The cytoplasmic tyrosine kinase c-Src is involved in
important cellular processes such as mitogenic signaling or cytoskeletal organization.
Substrates of the EGF-stimulated c-Src include the
EGFR itself, transcription factors of the Signal transducer
and activator of transcription family, such as Signal transducer and activator of
transcription 3 (STAT3), Shc,
cytoskeletal components and some other proteins .
EGFR via Janus kinase 1 and 2
(JAK1 and JAK2) complex with
STAT1 and STAT3 induces cell
EGF is one of modulators of epithelial-to-mesenchymal
transition (EMT). Excessive or inappropriate EGF stimulation
leads to EMT during tumor development , .
EGF leads to EMT during tissue development, for example
epicardial tissue . EGF in conjunction with
hydrocortisone induces EMT during postovulatory functional changes of ovarian surface
epithelium . Normally, EGF enhances
Transforming growth factor beta (TGF-beta) signaling and
induces EMT only in conjunction with TGF-beta 1 , , . The common pathway for
EGF-dependent EMT are ERK1/2
,  and PI3K 
activation. EGF via PI3K
activates Integrin-linked kinase
and Glycogen synthase kinase 3 beta (GSK3 beta) and
AKT-dependent activation of
Cyclin E and Cyclin-dependent
kinase 2 (Cdk2) and thus promotes proliferation during EMT.
Also, Via GSK3 beta-dependent manner, probably via
c-Jun (a protein of AP-1
complex)  promotes Matrix metallopeptidases
(MMP-2 and MMP-9) expression.
MMP expression usually initiated during EMT process .
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