title: Reciprocal regulation of Abl kinase by Crk Y251 and Abi1 controls invasive phenotypes in glioblastoma.
abstract: Crk is the prototypical member of a class of Src homology 2 (SH2) and Src homology 3 (SH3) domain-containing adaptor proteins that positively regulate cell motility via the activation of Rac1 and, in certain tumor types such as GBM, can promote cell invasion and metastasis by mechanisms that are not well understood. Here we demonstrate that Crk, via its phosphorylation at Tyr251, promotes invasive behavior of tumor cells, is a prominent feature in GBM, and correlating with aggressive glioma grade IV staging and overall poor survival outcomes. At the molecular level, Tyr251 phosphorylation of Crk is negatively regulated by Abi1, which competes for Crk binding to Abl and attenuates Abl transactivation. Together, these results show that Crk and Abi1 have reciprocal biological effects and act as a molecular rheostat to control Abl activation and cell invasion. Finally, these data suggest that Crk Tyr251 phosphorylation regulate invasive cell phenotypes and may serve as a biomarker for aggressive GBM.
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Sushil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Institute of Biophysics, School of Life Sciences, Wenzhou Medical University, Wenzhou, China.|Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical University, Wenzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Updesh
authors.initials: U
authors.lastname: Dixit
authors.affiliation: Departments of Urology and Biochemistry and Molecular Biology, SUNY Upstate Medical University, New York, NY, USA.
authors.forename: Sajjad
authors.initials: S
authors.lastname: Hossain
authors.affiliation: Institute of Biophysics, School of Life Sciences, Wenzhou Medical University, Wenzhou, China.
authors.forename: Yongzhang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Cell Signaling Technology, Danvers, MA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Cell Signaling Technology, Danvers, MA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hornbeck
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Sowalsky
authors.affiliation: Departments of Urology and Biochemistry and Molecular Biology, SUNY Upstate Medical University, New York, NY, USA.
authors.forename: Leszek
authors.initials: L
authors.lastname: Kotula
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Birge
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017209:Apoptosis; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010766:Phosphorylation; D011379:Prognosis; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D014945:Wound Healing
chemical_list: C513733:ABI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D003598:Cytoskeletal Proteins; D050737:Proto-Oncogene Proteins c-crk; D016315:Proto-Oncogene Proteins c-abl
keywords: Abi1; cell invasion; glioblastoma multiformae; non-canonical Crk signaling