title: PIKE mediates EGFR proliferative signaling in squamous cell carcinoma cells.
abstract: One of the key drivers for squamous cell carcinoma (SCC) proliferation is activation of the epidermal growth factor receptor (EGFR), a known proto-oncogene. However, the mechanism of EGFR-dependent SCC proliferation remains unclear. Our previous studies indicate that epidermal growth factor (EGF)-induced SCC cell proliferation requires the SH3 domain of phospholipase C-γ1 (PLC-γ1), but not its catalytic activity. The SH3 domain of PLC-γ1 is known to activate the short form of nuclear phosphatidylinositol 3-kinase enhancer (PIKE) that enhances the activity of nuclear class Ia phosphatidylinositol 3-kinase (PI3K) required for proliferation. However, PIKE has been described for more than a decade to be present exclusively in neuronal cells. In the present study, we found that PIKE was highly expressed in malignant human keratinocytes (SCC4 and SCC12B2) but had low expression in normal human keratinocytes. Immunohistochemical analysis showed strong nuclear staining of PIKE in human epidermal and tongue SCC specimens but little staining in the adjacent non-cancerous epithelium. Treatment of SCC4 cells with EGF-induced translocation of PLC-γ1 to the nucleus and binding of PLC-γ1 to the nuclear PIKE. Knockdown of PLC-γ1 or PIKE blocked EGF-induced activation of class Ia PI3K and protein kinase C-ζ and phosphorylation of nucleolin in the nucleus as well as EGF-induced SCC cell proliferation. However, inhibition of the catalytic activity of PLC-γ1 had little effect. These data suggest that PIKE has a critical role in EGF-induced SCC cell proliferation and may function as a proto-oncogene in SCC.
authors.affiliation: Institute of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China. Zhongjian.Xie@gmail.com
authors.forename: Z
authors.initials: Z
authors.lastname: Xie
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.forename: E-Y
authors.initials: EY
authors.lastname: Liao
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: S D
authors.initials: SD
authors.lastname: Pennypacker
authors.forename: J
authors.initials: J
authors.lastname: Peng
authors.forename: S M
authors.initials: SM
authors.lastname: Chang
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D016601:RNA-Binding Proteins / Q000378:metabolism; D012016:Reference Values; D015398:Signal Transduction; D014062:Tongue Neoplasms / Q000378:metabolism / Q000473:pathology; D018909:src Homology Domains; D000097796:Nucleolin; D000099221:Protein Kinase C zeta
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019204:GTP-Binding Proteins; D020690:GTPase-Activating Proteins; D058539:Phosphatidylinositol 3-Kinase; D051966:Phospholipase C gamma; D010750:Phosphoproteins; D011493:Protein Kinase C; D000090063:Proto-Oncogene Mas; D016601:RNA-Binding Proteins; D000097796:Nucleolin; D000099221:Protein Kinase C zeta; C000715470:MAS1 protein, human; C512478:EGFR protein, human; C485997:AGAP2 protein, human