Development - EGFR signaling pathway

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EGFR signaling pathway

Epidermal growth factor receptor (EGFR) belongs to the ERBB family of receptor tyrosine kinases that contains four closely related members EGFR and ERBB2-4. They couple the binding of the extracellular growth factor ligands to intracellular signaling pathways that regulate diverse biologic responses, including proliferation, 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), 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. However, it is the preferred heterodimeric partner for other EGFRs [1].

The ligand-induced receptor dimerization and subsequent autophosphorylation of distinct tyrosine residues creates docking sites for various membrane-targeted proteins. The cytoplasmic mediators that bind to EGFR phosphotyrosine residues are either the adaptor proteins, such as SHC transforming protein 1 (Shc), Growth factor receptor-bound protein 2 (GRB2), Cas-Br-M ecotropic retroviral transforming sequence (c-Cbl), Docking protein 2 (DOK2) and NCK adaptor protein 1 (NCK1), or enzymes, such as Phospholipase C gamma 1 (PLC-gamma 1), v-Src sarcoma viral oncogene homolog (c-Src) and PTK2 protein tyrosine kinase 2 (FAK1).

The adaptors Shc and GRB2 recruit the exchange factor Son of sevenless homolog 1 (SOS) and form the complex consisting of Shc, GRB2 and SOS. Activated SOS activates small GTPase v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) by its conversion from the inactive GDP-bounding state to the active GTP-bounding state. The activated H-Ras stimulates v-Raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1) / Mitogen-activated protein kinase 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 factors ELK1 member of ETS oncogene family (Elk-1), v-Myc myelocytomatosis viral oncogene homolog (c-Myc), and v-Fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos) [3].

The adaptor DOK2 associates with the GTPase-activating protein RAS p21 protein activator 1 (p120GAP) that reinforces intrinsic GTPase activity of H-Ras, thereby inactivating H-Ras. As a result, DOK2 can attenuate activation of the EGF-stimulated mitogen-activated protein kinase (MAPK) cascade [4].

The adaptor NCK1 couples EGFR stimulation to the activation of another MAPK-cascade, the JNK kinase cascade. NCK1 recruits p21-Activated kinase 1 (PAK1). NCK1/ PAK1 complex binds Mitogen-activated protein kinase kinase 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). The recruitment of the cascade to the activated membrane receptor localizes MLK2 on the plasma membrane where it is activated by its known upstream effectors, such as Ras-related C3 botulinum toxin substrate 1 (Rac1). Stimulation of JNK cascade results 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 the c-Cbl protein. c-Cbl is tyrosine-phosphorylated by tyrosine kinase upon stimulation via the EGF receptor. EGF stimulation induces the association of c-Cbl with the regulatory p85 subunit of the Phosphatidylinositol 3-kinase (PI3K reg class IA (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 plasma membrane and promotes the recruitment of proteins with pleckstrin homology (PH) domains. One of such proteins is serine/threonine kinase v-AKT murine thymoma viral oncogene homolog (AKT). It is the essential mediator of various cell processes, such as apoptosis, cell cycle, protein synthesis, regulation of metabolism [9].

Enzymes such as PLC-gamma 1 or the cytoplasmic tyrosine kinase c-Src tie EGFR activation to the generation of secondary messengers and calcium metabolism or to mitogenic signaling cascades, respectively. EGFR recruits and phosphorylates PLC-gamma 1 [10]. Phosphorylated PLC-gamma 1 generates Diacylglycerol (DAG) and Inositol-1,4,5-trisphosphate (IP3) from PtdIns(4,5)P2 [11]. DAG activates many isoforms of Protein kinase C (PKC), including conventional isoforms alpha, beta, and gamma (PKC-alpha, PKC-beta, and PKC-gamma), as well as PKC-epsilon and PKC-theta. PKC-alpha, PKC-beta, PKC-gamma, and PKC-epsilon phosphorylate and activate c-Raf-1, thereby amplifying H-Ras/ MEK1 and MEK2/ ERK1/2 kinase cascade [12], [13]. PKC-theta activates Nuclear factor NF-kappa-B inhibitor kinase beta (IKK-beta) resulting in activation of the Nuclear factor NF-kappa-B (NF-kB) [14].

The cytoplasmic tyrosine kinase c-Src is involved in important cellular processes such as mitogenic signaling or cytoskeletal organization. Substrates of the EGF-stimulated c-Src include the EGFR itself, transcription factors of the Signal transducer and activator of transcription family, such as Signal transducer and activator of transcription 3 (STAT3), Shc, cytoskeletal components and some other proteins [15].

EGFR via Janus kinase 1 and 2 (JAK1 and JAK2) complex with STAT1 and STAT3 induces cell migration [16]

EGF is one of modulators of epithelial-to-mesenchymal transition (EMT). Excessive or inappropriate EGF stimulation leads to EMT during tumor development [17], [18]. EGF leads to EMT during tissue development, for example epicardial tissue [19]. EGF in conjunction with hydrocortisone induces EMT during postovulatory functional changes of ovarian surface epithelium [20]. Normally, EGF enhances Transforming growth factor beta (TGF-beta) signaling and induces EMT only in conjunction with TGF-beta 1 [21], [22], [23]. The common pathway for EGF-dependent EMT are ERK1/2 [20], [21] and PI3K [22] activation. EGF via PI3K activates Integrin-linked kinase (ILK) signaling and Glycogen synthase kinase 3 beta (GSK3 beta) and AKT-dependent activation of Cyclin E and Cyclin-dependent kinase 2 (Cdk2) and thus promotes proliferation during EMT. Also, Via GSK3 beta-dependent manner, probably via c-Jun (a protein of AP-1 complex) [24] promotes Matrix metallopeptidases (MMP-2 and MMP-9) expression. MMP expression usually initiated during EMT process [20].

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. Prenzel N, Fischer OM, Streit S, Hart S, Ullrich A
    The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocrine-related cancer 2001 Mar;8(1):11-31
  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. Poitras L, Jean S, Islam N, Moss T
    PAK interacts with NCK and MLK2 to regulate the activation of jun N-terminal kinase. FEBS letters 2003 May 22;543(1-3):129-35
  6. Hirsch DD, Stork PJ
    Mitogen-activated protein kinase phosphatases inactivate stress-activated protein kinase pathways in vivo. The Journal of biological chemistry 1997 Feb 14;272(7):4568-75
  7. 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
  8. 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
  9. Brader S, Eccles SA
    Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori 2004 Jan-Feb;90(1):2-8
  10. Yarden Y, Sliwkowski MX
    Untangling the ErbB signalling network. Nature reviews. Molecular cell biology 2001 Feb;2(2):127-37
  11. Tkaczyk C, Beaven MA, Brachman SM, Metcalfe DD, Gilfillan AM
    The phospholipase C gamma 1-dependent pathway of Fc epsilon RI-mediated mast cell activation is regulated independently of phosphatidylinositol 3-kinase. The Journal of biological chemistry 2003 Nov 28;278(48):48474-84
  12. Hamilton M, Liao J, Cathcart MK, Wolfman A
    Constitutive association of c-N-Ras with c-Raf-1 and protein kinase C epsilon in latent signaling modules. The Journal of biological chemistry 2001 Aug 3;276(31):29079-90
  13. Sozeri O, Vollmer K, Liyanage M, Frith D, Kour G, Mark GE 3rd, Stabel S
    Activation of the c-Raf protein kinase by protein kinase C phosphorylation. Oncogene 1992 Nov;7(11):2259-62
  14. Altman A, Villalba M
    Protein kinase C-theta (PKCtheta): it's all about location, location, location. Immunological reviews 2003 Apr;192:53-63
  15. Silva CM
    Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene 2004 Oct 18;23(48):8017-23
  16. Andl CD, Mizushima T, Oyama K, Bowser M, Nakagawa H, Rustgi AK
    EGFR-induced cell migration is mediated predominantly by the JAK-STAT pathway in primary esophageal keratinocytes. American journal of physiology. Gastrointestinal and liver physiology 2004 Dec;287(6):G1227-37
  17. Lo HW, Hsu SC, Xia W, Cao X, Shih JY, Wei Y, Abbruzzese JL, Hortobagyi GN, Hung MC
    Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer research 2007 Oct 1;67(19):9066-76
  18. Barr S, Thomson S, Buck E, Russo S, Petti F, Sujka-Kwok I, Eyzaguirre A, Rosenfeld-Franklin M, Gibson NW, Miglarese M, Epstein D, Iwata KK, Haley JD
    Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal-like transitions. Clinical & experimental metastasis 2008;25(6):685-93
  19. Morabito CJ, Dettman RW, Kattan J, Collier JM, Bristow J
    Positive and negative regulation of epicardial-mesenchymal transformation during avian heart development. Developmental biology 2001 Jun 1;234(1):204-15
  20. Ahmed N, Maines-Bandiera S, Quinn MA, Unger WG, Dedhar S, Auersperg N
    Molecular pathways regulating EGF-induced epithelio-mesenchymal transition in human ovarian surface epithelium. American journal of physiology. Cell physiology 2006 Jun;290(6):C1532-42
  21. Grande M, Franzen A, Karlsson JO, Ericson LE, Heldin NE, Nilsson M
    Transforming growth factor-beta and epidermal growth factor synergistically stimulate epithelial to mesenchymal transition (EMT) through a MEK-dependent mechanism in primary cultured pig thyrocytes. Journal of cell science 2002 Nov 15;115(Pt 22):4227-36
  22. Docherty NG, O'Sullivan OE, Healy DA, Murphy M, O'neill AJ, Fitzpatrick JM, Watson RW
    TGF-beta1-induced EMT can occur independently of its proapoptotic effects and is aided by EGF receptor activation. American journal of physiology. Renal physiology 2006 May;290(5):F1202-12
  23. Tian YC, Chen YC, Chang CT, Hung CC, Wu MS, Phillips A, Yang CW
    Epidermal growth factor and transforming growth factor-beta1 enhance HK-2 cell migration through a synergistic increase of matrix metalloproteinase and sustained activation of ERK signaling pathway. Experimental cell research 2007 Jul 1;313(11):2367-77
  24. Troussard AA, Costello P, Yoganathan TN, Kumagai S, Roskelley CD, Dedhar S
    The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9). Oncogene 2000 Nov 16;19(48):5444-52

  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. Prenzel N, Fischer OM, Streit S, Hart S, Ullrich A
    The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocrine-related cancer 2001 Mar;8(1):11-31
  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. Poitras L, Jean S, Islam N, Moss T
    PAK interacts with NCK and MLK2 to regulate the activation of jun N-terminal kinase. FEBS letters 2003 May 22;543(1-3):129-35
  6. Hirsch DD, Stork PJ
    Mitogen-activated protein kinase phosphatases inactivate stress-activated protein kinase pathways in vivo. The Journal of biological chemistry 1997 Feb 14;272(7):4568-75
  7. 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
  8. 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
  9. Brader S, Eccles SA
    Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori 2004 Jan-Feb;90(1):2-8
  10. Yarden Y, Sliwkowski MX
    Untangling the ErbB signalling network. Nature reviews. Molecular cell biology 2001 Feb;2(2):127-37
  11. Tkaczyk C, Beaven MA, Brachman SM, Metcalfe DD, Gilfillan AM
    The phospholipase C gamma 1-dependent pathway of Fc epsilon RI-mediated mast cell activation is regulated independently of phosphatidylinositol 3-kinase. The Journal of biological chemistry 2003 Nov 28;278(48):48474-84
  12. Hamilton M, Liao J, Cathcart MK, Wolfman A
    Constitutive association of c-N-Ras with c-Raf-1 and protein kinase C epsilon in latent signaling modules. The Journal of biological chemistry 2001 Aug 3;276(31):29079-90
  13. Sozeri O, Vollmer K, Liyanage M, Frith D, Kour G, Mark GE 3rd, Stabel S
    Activation of the c-Raf protein kinase by protein kinase C phosphorylation. Oncogene 1992 Nov;7(11):2259-62
  14. Altman A, Villalba M
    Protein kinase C-theta (PKCtheta): it's all about location, location, location. Immunological reviews 2003 Apr;192:53-63
  15. Silva CM
    Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene 2004 Oct 18;23(48):8017-23
  16. Andl CD, Mizushima T, Oyama K, Bowser M, Nakagawa H, Rustgi AK
    EGFR-induced cell migration is mediated predominantly by the JAK-STAT pathway in primary esophageal keratinocytes. American journal of physiology. Gastrointestinal and liver physiology 2004 Dec;287(6):G1227-37
  17. Lo HW, Hsu SC, Xia W, Cao X, Shih JY, Wei Y, Abbruzzese JL, Hortobagyi GN, Hung MC
    Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer research 2007 Oct 1;67(19):9066-76
  18. Barr S, Thomson S, Buck E, Russo S, Petti F, Sujka-Kwok I, Eyzaguirre A, Rosenfeld-Franklin M, Gibson NW, Miglarese M, Epstein D, Iwata KK, Haley JD
    Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal-like transitions. Clinical & experimental metastasis 2008;25(6):685-93
  19. Morabito CJ, Dettman RW, Kattan J, Collier JM, Bristow J
    Positive and negative regulation of epicardial-mesenchymal transformation during avian heart development. Developmental biology 2001 Jun 1;234(1):204-15
  20. Ahmed N, Maines-Bandiera S, Quinn MA, Unger WG, Dedhar S, Auersperg N
    Molecular pathways regulating EGF-induced epithelio-mesenchymal transition in human ovarian surface epithelium. American journal of physiology. Cell physiology 2006 Jun;290(6):C1532-42
  21. Grande M, Franzen A, Karlsson JO, Ericson LE, Heldin NE, Nilsson M
    Transforming growth factor-beta and epidermal growth factor synergistically stimulate epithelial to mesenchymal transition (EMT) through a MEK-dependent mechanism in primary cultured pig thyrocytes. Journal of cell science 2002 Nov 15;115(Pt 22):4227-36
  22. Docherty NG, O'Sullivan OE, Healy DA, Murphy M, O'neill AJ, Fitzpatrick JM, Watson RW
    TGF-beta1-induced EMT can occur independently of its proapoptotic effects and is aided by EGF receptor activation. American journal of physiology. Renal physiology 2006 May;290(5):F1202-12
  23. Tian YC, Chen YC, Chang CT, Hung CC, Wu MS, Phillips A, Yang CW
    Epidermal growth factor and transforming growth factor-beta1 enhance HK-2 cell migration through a synergistic increase of matrix metalloproteinase and sustained activation of ERK signaling pathway. Experimental cell research 2007 Jul 1;313(11):2367-77
  24. Troussard AA, Costello P, Yoganathan TN, Kumagai S, Roskelley CD, Dedhar S
    The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9). Oncogene 2000 Nov 16;19(48):5444-52

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