title: Type I γ Phosphatidylinositol Phosphate 5-Kinase i5 Controls the Ubiquitination and Degradation of the Tumor Suppressor Mitogen-inducible Gene 6.
abstract: Mitogen-inducible gene 6 (Mig6) is a tumor suppressor, and the disruption of Mig6 expression is associated with cancer development. Mig6 directly interacts with epidermal growth factor receptor (EGFR) to suppress the activation and downstream signaling of EGFR. Therefore, loss of Mig6 enhances EGFR-mediated signaling and promotes EGFR-dependent carcinogenesis. The molecular mechanism modulating Mig6 expression in cancer remains unclear. Here we demonstrate that type I γ phosphatidylinositol phosphate 5-kinase i5 (PIPKIγi5), an enzyme producing phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), stabilizes Mig6 expression. Knockdown of PIPKIγi5 leads to the loss of Mig6 expression, which dramatically enhances and prolongs EGFR-mediated cell signaling. Loss of PIPKIγi5 significantly promotes Mig6 protein degradation via proteasomes, but it does not affect the Mig6 mRNA level. PIPKIγi5 directly interacts with the E3 ubiquitin ligase neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1). The C-terminal domain of PIPKIγi5 and the WW1 and WW2 domains of NEDD4-1 are required for their interaction. The C2 domain of NEDD4-1 is required for its interaction with PtdIns(4,5)P2By binding with NEDD4-1 and producing PtdIns(4,5)P2, PIPKIγi5 perturbs NEDD4-1-mediated Mig6 ubiquitination and the subsequent proteasomal degradation. Thus, loss of NEDD4-1 can rescue Mig6 expression in PIPKIγi5 knockdown cells. In this way, PIPKIγi5, NEDD4-1, and Mig6 form a novel molecular nexus that controls EGFR activation and downstream signaling.
authors.affiliation: From the Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298 and.
authors.forename: Ming
authors.initials: M
authors.lastname: Sun
authors.affiliation: From the Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298 and.
authors.forename: Jinyang
authors.initials: J
authors.lastname: Cai
authors.affiliation: the Molecular and Cellular Pharmacology Program, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin 53706.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
authors.affiliation: From the Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298 and ysun4@vcu.edu.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D000075702:Nedd4 Ubiquitin Protein Ligases; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D000072417:Protein Domains; D059748:Proteolysis; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C484017:ERRFI1 protein, human; D056827:Endosomal Sorting Complexes Required for Transport; D019269:Phosphatidylinositol 4,5-Diphosphate; D025521:Tumor Suppressor Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D044767:Ubiquitin-Protein Ligases; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: E3 ubiquitin ligase; Mig6; NEDD4-1; PIPKIγi5; cell signaling; epidermal growth factor receptor (EGFR); phosphatidylinositol phosphatase; tumor suppressor; ubiquitylation (ubiquitination)