Development - ERBB-family signaling

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].

References:

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