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Development ERBB-family signaling


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Development ERBB-family signaling

ERBB-family signaling

The ERBB family of receptor tyrosine kinases consists of four closely relatedmembers: Epidermal growth factor receptor ( EGFR, also known as ERBB1), v-erb-b2erythroblastic leukemia viral oncogene homolog 2, 3 and 4 ( ERBB2, ERBB3,and ERBB4 ). Binding of extracellular growth factor ligands is coupled withintracellular signaling pathways regulating diverse biologic responses, includingproliferation, differentiation, cell motility, and survival [1].

All ERBB receptors, excluding ERBB2, have their specific, partiallyoverlapping, ligands. EGF, Amphiregulin, Transforming growth factor alpha( TGF-alpha ) bind to EGFR only; Betacellulin, Heparin bindingEGF-like growth factor (HB-EGF ) and Epiregulin both bind EGFR andERBB4; the Neuregulins 1 and 2 ( NRG-1 and NRG-2 ) bind bothERBB3 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 theERBB 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 ERBB s, resulting inreceptor 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 andNuclear factor of kappa B ( NF-kB ) activation pathway.

ERBB s recruit p85 regulatory subunit of phosphatidylinositol-3-kinase (PI3K reg class 1A ) either directly (in case of ERBB3 and ERBB4 ) orvia adaptor proteins Growth factor receptor-bound protein 2 ( GRB2 ) and Cas-Br-M(murine) ecotropic retroviral transforming sequence ( c-Cbl ) , in case ofEGFR. Membrane-targeting catalytic subunit of PI3K ( PI3K cat class 1A )becomes active and converts Phosphoinositide 4,5-bisphosphate ( PtdIns(4,5)P2 ) toPhosphatidylinositol 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ), which is a secondmessenger involved in regulation various process [4].

EGFR and ERBB3 stimulate ERK kinase cascade. EGFR andERBB3 recruit Son of sevenless homolog ( SOS ) via adaptor proteinGRB2 and SHC transforming protein ( Shc ) , respectively. SOSis a guanine-nucleotide exchange factor for small GTPases, including H-Ras.H-Ras causes cascade of phosphorylation reactions that activate Transcriptionfactors ELK1 member of ETS oncogene family ( Elk-1 ), V-fos FBJ murineosteosarcoma viral oncogene homolog ( c-Fos ), and V-myc myelocytomatosis viraloncogene homolog ( c-Myc ) [5].

Adaptor protein Growth factor receptor-bound protein 7 ( GRB7 ) is involved inERBB-stimulated NF-kB pathway. GRB7 and Mitogen-activated protein kinase kinasekinase 14 ( NIK ) could be simultaneously recruited into signaling complexes ofall three receptors: EGFR, ERBB3, and ERBB4 [6].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 factorof kappa light polypeptide gene enhancer in B-cells inhibitor ( I-kB ), NF-kB is inactive as a transcription factor. Upon phosphorylation of I-kB byIKK, the inhibitor is degraded, allowing NF-kB to move to the nucleus andactivate the transcription of antiapoptotic proteins [7].