Development EGFR signaling pathway
EGFR signaling pathway
Epidermal growth factor receptor ( EGFR ) belongs to the ERBB family ofreceptor tyrosine kinases that contains four closely related members EGFR andERBB2-4. They couple the binding of the extracellular growth factor ligands tointracellular signaling pathways that regulate diverse biologic responses, includingproliferation, differentiation, cell motility, and survival [1].
Six ligands of EGFR are known. These are Epidermal growth factor ( EGF), Amphiregulin, Transforming growth factor alpha ( TGF-alpha ),Betacellulin, Heparin binding EGF-like growth factor ( HB-EGF ), andEpiregulin [2].
ErbB2 is a unique member of the ERBB family in that it does not bind any of theknown ligands with high affinity. However, it is the preferred heterodimeric partner forother EGFRs [1].
The ligand-induced receptor dimerization and subsequent autophosphorylation ofdistinct tyrosine residues creates docking sites for various membrane-targeted proteins.The cytoplasmic mediators that bind to EGFR phosphotyrosine residues are eitherthe adaptor proteins, such as SHC transforming protein 1 ( Shc ) , Growthfactor receptor-bound protein 2 ( GRB2 ) , Cas-Br-M ecotropic retroviraltransforming sequence ( c-Cbl ) , Docking protein 2 ( DOK2 ) and NCKadaptor protein 1 ( NCK1 ), or enzymes, such as Phospholipase C gamma 1 (PLC-gamma 1 ), v-Src sarcoma viral oncogene homolog ( c-Src ) and PTK2protein tyrosine kinase 2 ( FAK1 ).
The adaptors Shc and GRB2 recruit the exchange factor Son of sevenlesshomolog 1 ( SOS ) and form the complex consisting of Shc, GRB2 andSOS. Activated SOS activates small GTPase v-Ha-ras Harvey rat sarcomaviral oncogene homolog ( H-RAS ) by its conversion from the inactive GDP-boundingstate to the active GTP-bounding state. The activated H-RAS stimulates v-Raf-1murine leukemia viral oncogene homolog 1 ( c-Raf-1)/ Mitogen-activated proteinkinase kinase 1 and 2 ( MEK1 and MEK2 )/ Mitogen-activated protein kinase 1 and 3( ERK1/2 ) kinase cascade that leads to activation of the transcription factorsELK1 member of ETS oncogene family ( Elk-1 ), v-Myc myelocytomatosis viraloncogene homolog ( c-Myc ), and v-Fos FBJ murine osteosarcoma viral oncogenehomolog ( c-Fos ) [3].
The adaptor DOK2 associates with the GTPase-activating protein RAS p21 proteinactivator 1 ( p120GAP ) that reinforces intrinsic GTPase activity of H-RAS,thereby inactivating H-RAS. As a result, DOK2 can attenuate activation ofthe EGF-stimulated mitogen-activated protein kinase (MAPK) cascade [4].
The adaptor NCK1 couples EGFR stimulation to the activation of anotherMAPK-cascade, the JNK kinase cascade. NCK1 recruits p21-Activated kinase 1 (PAK1 ). NCK1/ PAK1 complex binds Mitogen-activated protein kinasekinase kinase 10 ( MLK2 ) and activates the JNK cascade consisting of MLK2/ Mitogen-activated protein kinase kinase 4 and 7 ( MEK4 and MKK7 )/ Mitogen-activated protein kinase 8 and 9 ( JNK1 and JNK2 ). Therecruitment of the cascade to the activated membrane receptor localizes MLK2 onthe plasma membrane where it is activated by its known upstream effectors, such asRas-related C3 botulinum toxin substrate 1 ( Rac1 ). Stimulation of JNK cascaderesults in activation of the transcription factors Elk-1, Jun oncogene (c-Jun ) and some others [5]. Dual specificity phosphatases 1 and 4 (MKP-1 and MKP-2 ) attenuate activation of the JNK cascade [6].
The adaptor GRB2 also binds via its SH3 domain with proline-rich regions of thec-Cbl protein. c-Cbl is tyrosine-phosphorylated by tyrosine kinase uponstimulation via the EGF receptor. EGF stimulation induces the association of c-Cblwith the regulatory p85 subunit of the Phosphatidylinositol 3-kinase ( PI3K reg classIA (p85) ) [7].
Activated PI3K cat class IA converts Phosphatidylinositol 4,5-biphosphate(PtdIns(4,5)P2) to Phosphatidylinositol 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ).The latter is a second messenger involved in regulation of various processes [8]. PtdIns(3,4,5)P3 associates with the inner surface of the plasmamembrane and promotes the recruitment of proteins with pleckstrin homology (PH) domains.One of such proteins is serine/threonine kinase v-AKT murine thymoma viral oncogenehomolog ( AKT ). It is the essential mediator of various cell processes, such asapoptosis, cell cycle, protein synthesis, regulation of metabolism [9].
Enzymes such as PLC-gamma 1 or the cytoplasmic tyrosine kinase c-Srctie EGFR activation to the generation of secondary messengers and calciummetabolism or to mitogenic signaling cascades, respectively. EGFR recruits andphosphorylates PLC-gamma 1 [10].
Phosphorylated PLC-gamma 1 generates Diacylglycerol ( DAG ) andInositol-1,4,5-trisphosphate ( IP3 ) from PtdIns(4,5)P2 [11].
DAG activates many isoforms of protein kinase C (PKC), including conventionalisoforms alpha, beta, and gamma ( PKC-alpha, PKC-beta, and PKC-gamma ), as well asPKC-epsilon and PKC-theta. PKC-alpha, PKC-beta, PKC-gamma, andPKC-epsilon phosphorylate and activate c- Raf-1, thereby amplifying H-RAS/MEK1 and MEK2/ ERK1/2 kinase cascade [12], [13]. PKC-thetaactivates Nuclear factor NF-kappa-B inhibitor kinase beta (IKK-beta) resulting inactivation of the Nuclear factor NF-kappa-B ( NF-kB ) [14].
The cytoplasmic tyrosine kinase c-Src is involved in important cellularprocesses such as mitogenic signaling or cytoskeletal organization. Substrates of theEGF-stimulated c-Src include the EGFR itself, transcription factors of theSignal transducer and activator of transcription family, such as STAT3,Shc, cytoskeletal components and some other proteins [15].
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