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Development EGFR signaling via small GTPases

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Development EGFR signaling via small GTPases

EGFR signaling via small GTPase

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

Six EGFR ligands have been identified including Epidermal growth factor ( EGF), Amphiregulin, TGF-alpha; Betacellulin, HB-EGF (heparin binding EGF-like growthfactor), and Epiregulin [2].

ERBB2 is a unique member of the ERBB family in that it does not bind any of theknown ligands with high affinity, but it is the preferred heterodimeric partner for otherEGFR [1].

The ligand-induced receptor dimerization and subsequent autophosphorylation ofdistinct 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 ), andEpidermal growth factor receptor pathway substrate 8 ( EPS8 ) . Adaptorproteins mediate various signaling cascades, initiated by EGFR.

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

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

The adaptor DOK2 associates with the GTPase-activating protein RAS p21 proteinactivator (GTPase activating protein) 1 ( p120GAP ), which reinforces intrinsicGTPase activity of RAS-proteins, thereby inactivating them. Thus DOK2 couldattenuate 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 kinases8-10 ( JNK(MAPK8-10) ). EPS8 is a substrate of the EGFR. EPS8complexes with SOS by the Abl-interactor 1 ( E3b1(ABI-1) ) and mediatesactivation of Rac1.

EGFRs regulate their own internalization via GTP-binding proteins Rab-family.EPS8 interacts with USP6 N-terminal like ( RNTRE ) , which is aRAB5A, member RAS oncogene family ( Rab-5A ) GTPase-activating protein. Byentering in a complex with EPS8, RNTRE acts on Rab-5A and inhibitsinternalization of the EGFR. Furthermore, RNTRE diverts EPS8 fromits 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 traffickingthrough Rab-5A [5].

Another pathway mediated by Rac1 activation includes the activation of thePhosphatidylinositol 3-kinase (PI3K) cascade. EGF stimulation induces associationof c-Cbl, complexed to the adapter protein Grb2, withPhosphoinositide-3-kinase, regulatory ( PI3K reg class IA ) thereby activatingPhosphoinositide-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 membranepromoting the recruitment of proteins with pleckstrin homology (PH) domains, includingthe Vav 2 guanine nucleotide exchange factor ( VAV-2 ), which activates the Rhofamily of Ras-related GTPases, such as Rac1 [8].