Pathway Map Details

Development_EGFR signaling via small GTPases



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JNK(MAPK8-10), RAC1, EGFR, EPS8, c-CBL, K-RAS, MLK2(MAP3K10), PtdIns(4,5)P2, c-Myc, GRB2, ERBB2, SOS, H-Ras, MEK1/2, SOS, 2.7.1.137, MKK4/7, p120GAP, RNTRE, Shc, PI3K reg class IA, N-RAS, DOK2, c-Fos, E3b1(ABI-1), PtdIns(3,4,5)P3, EGF, PI3K cat class IA, c-Raf-1, Elk-1, Rab-5A, ERK1/2, VAV-2

Description:

EGFR signaling via small GTPase

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 in that it does not bind any of the known ligands with high affinity, but it is the preferred heterodimeric partner for other EGFR [1].

The 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 ), SHC (Src homology 2 domain containing) transforming protein 1 ( Shc ), Docking protein 2, 56kDa ( DOK2 ), and Epidermal growth factor receptor pathway substrate 8 ( EPS8 ) . Adaptor proteins mediate various signaling cascades, initiated by EGFR.

A set of cascades are mediated by small GTPases. One such pathway leads to MAP kinase activation. This pathway involves Shc, Grb2, Son of Sevenless homologs ( SOS ), Harvey rat sarcoma viral oncogene homolog ( H-Ras ), Neuroblastoma RAS viral (v-ras) oncogene homolog ( N-Ras), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( K-Ras ).

Adaptors Shc and Grb2 recruit exchange factors on of SOS, forming protein complex consisting of Shc/ Grb2/ SOS. Activated SOS activates small GTPases H-RAS, N-RAS, K-RAS by convertingit from inactive GDP-bound state to active GTP-bound state. Activated RAS-proteins stimulate v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinases 1 and 2 ( MEK1(MAP2K1) MEK2(MAP2K2) ) / Mitogen-activated protein kinase 1-3 ( ERK1/2 ) cascade, which lead to activation transcription factors ELK1, member of ETS oncogene family ( Elk-1 ), v-myc myelocytomatosis viral oncogene homolog ( c-Myc ), v-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) [3].

The adaptor DOK2 associates with the GTPase-activating protein RAS p21 protein activator (GTPase activating protein) 1 ( p120GAP ), which reinforces intrinsic GTPase activity of RAS-proteins, thereby inactivating them. Thus DOK2 could attenuate EGF -stimulated mitogen-activated protein (MAP) kinase activation [4].

Another pathway involving the Ras-related C3 botulinum toxin substrate 1 ( Rac1 ), includes mitogen-induced cytoskeletal changes and Mitogen-activated protein kinases 8-10 ( JNK(MAPK8-10) ). EPS8 is a substrate of the EGFR. EPS8 complexes with SOS by the Abl-interactor 1 ( E3b1(ABI-1) ) and mediates activation of Rac1.

EGFRs regulate their own internalization via GTP-binding proteins Rab-family. EPS8 interacts with USP6 N-terminal like ( RNTRE ) , which is a RAB5A, member RAS oncogene family ( Rab-5A ) GTPase-activating protein. By entering in a complex with EPS8, RNTRE acts on Rab-5A and inhibits internalization of the EGFR. Furthermore, RNTRE diverts EPS8 from its Rac-activating function, resulting in the attenuation of Rac signaling. Thus, depending on its state of association with E3b1(ABI-1) or RNTRE, EPS8 participates in both EGFR signaling through Rac1, and trafficking through Rab-5A [5].

Another pathway mediated by Rac1 activation includes the activation of the Phosphatidylinositol 3-kinase (PI3K) cascade. EGF stimulation induces association of c-Cbl, complexed to the adapter protein Grb2, with Phosphoinositide-3-kinase, regulatory ( PI3K reg class IA ) thereby activating Phosphoinositide-3-kinase catalytic subunit ( PI3K cat class IA ) [6].

Activated PI3K cat class IA converts inositol 4,5-biphosphate ( PtdIns(4,5)P2 ) into inositol 3,4,5-trisphosphate ( PtdIns(3,4,5)P3 ), which is a secondary messenger involved in regulation various processes [7]. PtdIns(3,4,5)P3 associates with the inner lipid bilayer of the plasma membrane promoting the recruitment of proteins with pleckstrin homology (PH) domains, including the Vav 2 guanine nucleotide exchange factor ( VAV-2 ), which activates the Rho family of Ras-related GTPases, such as Rac1 [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. Ehrhardt A, David MD, Ehrhardt GR, Schrader JW
    Distinct mechanisms determine the patterns of differential activation of H-Ras, N-Ras, K-Ras 4B, and M-Ras by receptors for growth factors or antigen. Molecular and cellular biology 2004 Jul;24(14):6311-23
  4. Jones N, Dumont DJ
    Recruitment of Dok-R to the EGF receptor through its PTB domain is required for attenuation of Erk MAP kinase activation. Current biology : CB 1999 Sep 23;9(18):1057-60
  5. Lanzetti L, Rybin V, Malabarba MG, Christoforidis S, Scita G, Zerial M, Di Fiore PP
    The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5. Nature 2000 Nov 16;408(6810):374-7
  6. 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
  7. 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
  8. 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