Development - ERBB-family signaling

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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:

  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. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
    Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
  5. Brader S, Eccles SA
    Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori 2004 Jan-Feb;90(1):2-8
  6. Yarden Y, Sliwkowski MX
    Untangling the ErbB signalling network. Nature reviews. Molecular cell biology 2001 Feb;2(2):127-37
  7. 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
  8. 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

  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. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
    Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
  5. Brader S, Eccles SA
    Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori 2004 Jan-Feb;90(1):2-8
  6. Yarden Y, Sliwkowski MX
    Untangling the ErbB signalling network. Nature reviews. Molecular cell biology 2001 Feb;2(2):127-37
  7. 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
  8. 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

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