Development - EGFR signaling via PIP3

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EGFR signaling via PIP3

The Epidermal growth factor receptor (EGFR) belongs to the ERBB family of receptor tyrosine kinases, which consists of four closely related members: EGFR and v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (ERBB2), ERBB3 and ERBB4. These receptors couple binding of extracellular growth factor ligands to intracellular signaling pathways and regulate diverse biologic responses, including proliferation, differentiation, cell motility, and survival [1].

Six EGFR ligands have been identified including Epidermal growth factor (EGF), Amphiregulin, TGF-alpha; Betacellulin, HB-EGF (heparin binding EGF-like growth factor), and Epiregulin [2]. ERBB2 is a unique member of the ErbB family as it does not bind any of the known ligands with high affinity, but it is the preferred heterodimeric partner for other EGFRs [1].

Ligand-induced receptor dimerization and subsequent autophosphorylation of distinct tyrosine residues creates docking sites for various membrane-targeted proteins, including adaptor proteins Growth factor receptor-bound protein 2 (Grb2), Cas-Br-M (murine) ecotropic retroviral transforming sequence (c-Cbl), GRB2-associated binding protein 1 (GAB1), Insulin receptor substrates 1 and 2 (IRS-1 and IRS-2), GRB7, and DOK2.

One signaling cascade stimulated by EGF is the Phosphatidylinositol 3-kinase (PI3K) - pathway. EGFR can recruit Phosphoinositide-3-kinase, regulatory subunit (PI3K reg class IA) via set of adaptor protein, such as c-Cbl, GAB1, IRS-1 and IRS-2 [3], [4].

c-Cbl is a target of tyrosine phosphorylation upon stimulation through the EGFR tyrosine kinase activity. c-Cbl can also form protein-protein interactions with through its proline-rich regions with SH3 domain of adaptor proteins such as Grb2, which also is recruited by EGFR [5].

The activated Phosphoinositide-3-kinase, catalytic (PI3K cat class IA) converts phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2) to phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3), which is a secondary messenger involved in the regulation of various process [6]. PtdIns(3,4,5)P3 associates with the inner lipid bilayer of the plasma membrane to promote the recruitment of proteins with pleckstrin homology (PH) domains. One of them is v-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)), which is a crucial mediator of various cell process, such as apoptosis, cell cycle, protein synthesis, regulation of metabolism [7].

Adaptor proteins such as GAB1, IRS-1, IRS-2 also have pleckstrin homology domains and are recruited by PtdIns(3,4,5)P3 to the membrane creating a positive feedback regulatory loop [8].

Another protein with a pleckstrin homology domain is Vav 2 guanine nucleotide exchange factor (VAV-2), which activates the Rho family of Ras-related GTPases, such as Ras-related C3 botulinum toxin substrate 1 (Rac1). Activated EGFR phosphorylates VAV-2, but this does not correlate with tyrosine phosphorylation of VAV-2. EGF regulates the VAV-2 activity basically through PI3K activation, whereas tyrosine phosphorylation of VAV-2 is required for mediating protein-protein interactions [9].

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. Fujioka T, Kim JH, Adachi H, Saito K, Tsujimoto M, Yokoyama S, Ui M
    Further evidence for the involvement of insulin receptor substrates in epidermal growth factor-induced activation of phosphatidylinositol 3-kinase. European journal of biochemistry / FEBS 2001 Aug;268(15):4158-68
  4. Onishi-Haraikawa Y, Funaki M, Gotoh N, Shibuya M, Inukai K, Katagiri H, Fukushima Y, Anai M, Ogihara T, Sakoda H, Ono H, Kikuchi M, Oka Y, Asano T
    Unique phosphorylation mechanism of Gab1 using PI 3-kinase as an adaptor protein. Biochemical and biophysical research communications 2001 Oct 26;288(2):476-82
  5. Fukazawa T, Miyake S, Band V, Band H
    Tyrosine phosphorylation of Cbl upon epidermal growth factor (EGF) stimulation and its association with EGF receptor and downstream signaling proteins. The Journal of biological chemistry 1996 Jun 14;271(24):14554-9
  6. 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
  7. Brader S, Eccles SA
    Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori 2004 Jan-Feb;90(1):2-8
  8. Razzini G, Ingrosso A, Brancaccio A, Sciacchitano S, Esposito DL, Falasca M
    Different subcellular localization and phosphoinositides binding of insulin receptor substrate protein pleckstrin homology domains. Molecular endocrinology (Baltimore, Md.) 2000 Jun;14(6):823-36
  9. Tamas P, Solti Z, Bauer P, Illes A, Sipeki S, Bauer A, Farago A, Downward J, Buday L
    Mechanism of epidermal growth factor regulation of Vav2, a guanine nucleotide exchange factor for Rac. The Journal of biological chemistry 2003 Feb 14;278(7):5163-71

  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. Fujioka T, Kim JH, Adachi H, Saito K, Tsujimoto M, Yokoyama S, Ui M
    Further evidence for the involvement of insulin receptor substrates in epidermal growth factor-induced activation of phosphatidylinositol 3-kinase. European journal of biochemistry / FEBS 2001 Aug;268(15):4158-68
  4. Onishi-Haraikawa Y, Funaki M, Gotoh N, Shibuya M, Inukai K, Katagiri H, Fukushima Y, Anai M, Ogihara T, Sakoda H, Ono H, Kikuchi M, Oka Y, Asano T
    Unique phosphorylation mechanism of Gab1 using PI 3-kinase as an adaptor protein. Biochemical and biophysical research communications 2001 Oct 26;288(2):476-82
  5. Fukazawa T, Miyake S, Band V, Band H
    Tyrosine phosphorylation of Cbl upon epidermal growth factor (EGF) stimulation and its association with EGF receptor and downstream signaling proteins. The Journal of biological chemistry 1996 Jun 14;271(24):14554-9
  6. 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
  7. Brader S, Eccles SA
    Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori 2004 Jan-Feb;90(1):2-8
  8. Razzini G, Ingrosso A, Brancaccio A, Sciacchitano S, Esposito DL, Falasca M
    Different subcellular localization and phosphoinositides binding of insulin receptor substrate protein pleckstrin homology domains. Molecular endocrinology (Baltimore, Md.) 2000 Jun;14(6):823-36
  9. Tamas P, Solti Z, Bauer P, Illes A, Sipeki S, Bauer A, Farago A, Downward J, Buday L
    Mechanism of epidermal growth factor regulation of Vav2, a guanine nucleotide exchange factor for Rac. The Journal of biological chemistry 2003 Feb 14;278(7):5163-71

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