title: PTEN is a protein tyrosine phosphatase for IRS1.
abstract: The biological function of the PTEN tumor suppressor is mainly attributed to its lipid phosphatase activity. This study demonstrates that mammalian PTEN is a protein tyrosine phosphatase that selectively dephosphorylates insulin receptor substrate-1 (IRS1), a mediator of insulin and IGF signals. IGF signaling was defective in cells lacking NEDD4, a PTEN ubiquitin ligase, whereas AKT activation triggered by EGF or serum was unimpaired. Defective IGF signaling caused by NEDD4 deletion, including phosphorylation of IRS1 and AKT, was rescued by PTEN ablation. We demonstrate the nature of PTEN as an IRS1 phosphatase by direct biochemical analysis and cellular reconstitution, showing that NEDD4 supports insulin-mediated glucose metabolism and is required for the proliferation of IGF1 receptor-dependent but not EGF receptor-dependent tumor cells. Thus, PTEN is a protein phosphatase for IRS1, and its antagonism by NEDD4 promotes signaling by IGF and insulin.
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Junru
authors.initials: J
authors.lastname: Wang
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Cross
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Thompson
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D051379:Mice; D000075702:Nedd4 Ubiquitin Protein Ligases; D051059:PTEN Phosphohydrolase / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics; D013002:Somatomedins / Q000378:metabolism / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D013002:Somatomedins; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse