ERBB RECEPTORS SIGNALING PATHWAY

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Epidermal growth factor receptor (EGFR) family members including EGFR, ErbB2 (Neu, HER2), ErbB3, and ErbB4 play a critical role in cancer development (8). Signal transduction by ErbB family receptors involves an array of ten possible homodimeric and heterodimeric combinations diversifying biologic responses to ligands of the EGF and the neuregulin (NRG) family (9). Upon ligand binding, ErbB receptors undergo dimerization and receptor trans-phosphorylation. ErbB3 lacks of intrinsic kinase activity, while ErbB2 appears to have no direct ligand (8). These events lead to the activation of the receptor tyrosine kinase which then activates by phosphorylation the downstream effector enzymes phospholipase C gamma (PLCg), phosphatidylinositol 3-kinase (PI3K) and Src, and binds the adaptor proteins Grb2 and Shc, which contain multiple protein interaction motifs able to recruit and activate the RAS GTPase (8). PLCg induces the formation of diacylglycerol, which triggers the serine-threonine kinase protein kinase C (PKC), which in turn activates various transcription factors. PI3K activates the kinase Akt (protein kinase B), which is involved in cell proliferation and inhibition of apoptosis (10). RAS proteins activate RAF kinases which initiate a phosphorylation cascade, which activates the classical mitogen-activated protein kinases (MAPKs) signaling pathway up to the extracellular signal regulated kinases 1 and 2 (ERK1/2) which translocate to the nucleus and activate several transcription factors, including activator protein-1 (AP-1), c-Myc, etc. (10). The MAPK/ERK pathway represents one of the major signaling cascades regulating cell proliferation. Other terminal serine/threonine kinases include c-Jun amino-terminal kinases (JNK1/2/3), p38 kinases and ERK which are activated by stress and growth factors (10). JNK and p38 kinases mainly regulate cell differentiation and apoptosis (10). Given the established role of abnormal ErbB receptors activation in tumor cell proliferation, survival and metastasis, many efforts are currently made to identify drugs that inhibit their signaling pathway (11-16). In addition, ErbB2 oncogenic potential combined with the high level overexpression in tumor tissue and cell surface localization render this receptor a suitable target for immunotherapeutic approaches (17-28). The principal ErbB receptors-mediated signaling pathways are illustrated in Figure 1, panel A.