Pathway Map Details

Development_ERBB-family signaling



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Object list (links open in MetaCore):

GRB7, Neuregulin 4, c-Raf-1, Neuregulin 3, Betacellulin, IKK (cat), IKK-gamma, HB-EGF, PLC-gamma 1, NF-kB, Epiregulin, MEK1/2, Shc, PI3K cat class IA, Neuregulin 2, ERBB4, Elk-1, c-Cbl, H-Ras, NIK(MAP3K14), SOS, 2.7.1.137, PI3K reg class IA, c-Myc, EGF, PtdIns(4,5)P2, I-KB, GRB2, ERBB3, ERBB2, Amphiregulin, TGF-alpha, PtdIns(3,4,5)P3, Neuregulin 1, AKT(PKB), c-Fos, EGFR, ERK1/2

Description:

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 ERBB s, 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.

ERBB s 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].

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 ) [5].

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 [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 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 [7].

References:

  1. Marmor MD, Skaria KB, Yarden Y
    Signal transduction and oncogenesis by ErbB/HER receptors. International journal of radiation oncology, biology, physics 2004 Mar 1;58(3):903-13
  2. Sweeney C, Carraway KL 3rd
    Ligand discrimination by ErbB receptors: differential signaling through differential phosphorylation site usage. Oncogene 2000 Nov 20;19(49):5568-73
  3. Schlessinger J
    Cell signaling by receptor tyrosine kinases. Cell 2000 Oct 13;103(2):211-25
  4. Brader S, Eccles SA
    Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori 2004 Jan-Feb;90(1):2-8
  5. Yarden Y, Sliwkowski MX
    Untangling the ErbB signalling network. Nature reviews. Molecular cell biology. 2001 Feb;2(2):127-37
  6. Chen D, Xu LG, Chen L, Li L, Zhai Z, Shu HB
    NIK is a component of the EGF/heregulin receptor signaling complexes. Oncogene 2003 Jul 10;22(28):4348-55
  7. Agarwal A, Das K, Lerner N, Sathe S, Cicek M, Casey G, Sizemore N
    The AKT/I kappa B kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-kappa B and beta-catenin. Oncogene 2005 Feb 3;24(6):1021-31