title: Regulation of paxillin-p130-PI3K-AKT signaling axis by Src and PTPRT impacts colon tumorigenesis.
abstract: Protein tyrosine phosphatase receptor T (PTPRT) is frequently mutated in a variety of human cancers including colorectal cancer. Here we report that PTPRT knockout increases the size of mouse colon tumors in the Apcmin+/- genetic background, suggesting that inactivation of PTPRT promotes tumor progression. We previously demonstrated that PTPRT dephosphorylates paxillin at tyrosine-Y88 residue. Consistently, phosphorylation of Y88 paxillin (pY88) is up-regulated in colon tumors derived from Apcmin+/- Ptprt-/- mice. An important downstream effector of pY88 paxillin is the oncogene Akt. Here, we show that pY88 paxillin impacts the Akt pathway by regulating the interaction between p130cas and the p85 regulatory subunit of PI3-Kinase. Additionally, while pY88 paxillin is a substrate of the tumor suppressor phosphatase PTPRT, the corresponding kinase has not been previously identified. In this study, we demonstrate that the oncogenic kinase Src directly phosphorylates paxillin at Y88. Moreover, colorectal cancer cells that express high levels of pY88 paxillin are sensitive to dasatinib treatment, suggesting that pY88 paxillin may serve as a predictive biomarker for Src family kinase inhibitors.
authors.affiliation: Department of Genetics and Genome Sciences, Case Medical Center and Case Western Reserve University, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Genetics and Genome Sciences, Case Medical Center and Case Western Reserve University, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Scott
authors.affiliation: Department of Genetics and Genome Sciences, Case Medical Center and Case Western Reserve University, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Genetics and Genome Sciences, Case Medical Center and Case Western Reserve University, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Department of Genetics and Genome Sciences, Case Medical Center and Case Western Reserve University, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Xiujing
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Genetics and Genome Sciences, Case Medical Center and Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Saigopal
authors.initials: S
authors.lastname: Somasundaram
authors.affiliation: Department of Genetics and Genome Sciences, Case Medical Center and Case Western Reserve University, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Ahmad M
authors.initials: AM
authors.lastname: Khalil
authors.affiliation: Department of Pathology, Case Medical Center and Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Willis
authors.affiliation: Department of Genetics and Genome Sciences, Case Medical Center and Case Western Reserve University, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Zhenghe
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D000069439:Dasatinib / Q000494:pharmacology; D005260:Female; D017491:Genes, APC; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D053842:Microsatellite Instability; D008954:Models, Biological; D009367:Neoplasm Staging; D051419:Paxillin / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D050719:Crk-Associated Substrate Protein; D051419:Paxillin; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; C516865:PTPRT protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D000069439:Dasatinib
keywords: PTPRT; Src; colorectal cancer; paxillin