The ERBB family of receptor tyrosine kinases consists of
four closely related members: Epidermal growth factor receptor
(EGFR, also known as ERBB1), v-erb-b2 erythroblastic
leukemia viral oncogene homolog 2, 3 and 4 (ERBB2,
ERBB3, and ERBB4). Binding of
extracellular growth factor ligands is coupled with intracellular signaling pathways
regulating diverse biologic responses, including proliferation, differentiation, cell
motility, and survival .
All ERBB receptors, excluding
ERBB2, have their specific, partially overlapping, ligands.
EGF, Amphiregulin, Transforming
growth factor alpha (TGF-alpha) bind to
EGFR only; Betacellulin,
Heparin binding EGF-like growth factor (HB-EGF) and
Epiregulin both bind EGFR and
ERBB4; the Neuregulins 1 and 2
(NRG-1 and NRG-2) bind both
ERBB3 and ERBB4; and
NRG-3 and NRG-4 bind only
ERBB4 , , .
No known ligand binds ERBB2. ERBB2
is a unique member of the ERBB family in that
it does not bind any of the known ligands with high affinity, but it is the preferred
heterodimeric partner for other ERBB- receptors .
Ligand binding induces homo- or heterodimerization of
ERBBs, resulting in receptor transphosphorylation, which
significantly enhances kinase activity.
Activation of receptors stimulates three generic cascades: Phosphoinositide-3-kinase
(PI3K)/V-akt murine thymoma
viral oncogene homolog 1 (AKT(PKB)).signaling cascade,
V-Ha-ras Harvey rat sarcoma viral oncogene homolog
Mitogen-activated protein kinase 3/1 (ERK1/2)
kinase cascade and Nuclear factor of kappa B (NF-kB)
ERBBs recruit p85 regulatory subunit of
phosphatidylinositol-3-kinase (PI3K reg class 1A) either
directly (in case of ERBB3 and
ERBB4) or via adaptor proteins Growth factor receptor-bound protein 2
(GRB2) and Cas-Br-M (murine) ecotropic retroviral
transforming sequence (c-Cbl),
in case of EGFR. Membrane-targeting catalytic subunit of
PI3K (PI3K cat class 1A) becomes active and converts
Phosphoinositide 4,5-bisphosphate (PtdIns(4,5)P2) to
Phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3),
which is a second messenger involved in regulation various process .
PtdIns(3,4,5)P3 associates with the inner surface of plasma
membrane promoting recruitment of proteins with pleckstrin homology (PH) domains. One of
them is AKT, which is a crucial mediator of various cell
process, such as apoptosis, cell cycle, protein synthesis, and regulation of metabolism
EGFR and ERBB3 stimulate
ERK kinase cascade. EGFR and
ERBB3 recruit Son of sevenless homolog
(SOS) via adaptor protein GRB2
and SHC transforming protein
SOS is a guanine-nucleotide exchange factor for small
GTPases, including H-Ras. H-Ras
causes cascade of phosphorylation reactions that activate Transcription factors ELK1
member of ETS oncogene family (Elk-1), V-fos FBJ murine
osteosarcoma viral oncogene homolog (c-Fos), and V-myc
myelocytomatosis viral oncogene homolog
Adaptor protein Growth factor receptor-bound protein 7
(GRB7) is involved in ERBB-stimulated NF-kB pathway.
GRB7 and Mitogen-activated protein kinase kinase kinase 14
(NIK) could be simultaneously recruited into signaling
complexes of all three receptors: EGFR,
ERBB3, and ERBB4 . NIK phosphorylates and activates Catalytic
subunits of the I-kappa-B kinase (IKK (cat)) that regulates
the activity of the Nuclear factor-kappa B (NF-kB)
transcription factor. When bound to its cytosolic inhibitor Nuclear factor of kappa light
polypeptide gene enhancer in B-cells inhibitor (I-kB),
NF-kB is inactive as a transcription factor. Upon
phosphorylation of I-kB by IKK,
the inhibitor is degraded, allowing NF-kB to move to the
nucleus and activate the transcription of antiapoptotic proteins .
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