Pathway maps

Development_EGFR signaling via PIP3
Development_EGFR signaling via PIP3

Object List (links open in MetaCore):

PI3K cat class IA, MKK4/7, RAC1, GRB2, 2.7.1.137, PIP2, AKT(PKB), VAV-2, PI3K reg class IA, IRS-2, IRS-1, PIP3, 3.1.3.67, PTEN, GAB1, JNK(MAPK8-10), ERBB2, EGFR, MLK2(MAP3K10), EGF, c-Cbl, PDK (PDPK1)

Description

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