ERBB-family signaling
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 [1].
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 [1], [2], [3].
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 [1].
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
(H-Ras)-dependent
Mitogen-activated protein kinase 3/1 (ERK1/2)
kinase cascade and Nuclear factor of kappa B (NF-kB)
activation pathway.
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 [4].
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
[5].
EGFR and ERBB3 stimulate
ERK kinase cascade. EGFR and
ERBB3 recruit Son of sevenless homolog
(SOS) via adaptor protein GRB2
and SHC transforming protein
(Shc), respectively.
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
(c-Myc) [6].
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 [7]. 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 [8].
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Signal transduction and oncogenesis by ErbB/HER receptors.
International journal of radiation oncology, biology, physics 2004 Mar 1;58(3):903-13
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Ligand discrimination by ErbB receptors: differential signaling through differential phosphorylation site usage.
Oncogene 2000 Nov 20;19(49):5568-73
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Cell signaling by receptor tyrosine kinases.
Cell 2000 Oct 13;103(2):211-25
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Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer.
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NIK is a component of the EGF/heregulin receptor signaling complexes.
Oncogene 2003 Jul 10;22(28):4348-55
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The AKT/I kappa B kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-kappa B and beta-catenin.
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