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	Sushil Kumar, Bin Lu, Updesh Dixit, Sajjad Hossain, Yongzhang Liu, Jing Li, Peter Hornbeck, Weiming Zheng, Adam G Sowalsky, Leszek Kotula, Raymond B Birge
Journal	Oncotarget (Oncotarget) Vol. 6 Issue 35 Pg. 37792-807 (Nov 10 2015) ISSN: 1949-2553 [Electronic] United States
PMID	26473374 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	ABI1 protein, human Adaptor Proteins, Signal Transducing Biomarkers, Tumor Cytoskeletal Proteins Proto-Oncogene Proteins c-crk Proto-Oncogene Proteins c-abl
Topics	Adaptor Proteins, Signal Transducing (metabolism) Apoptosis Binding Sites Biomarkers, Tumor (metabolism) Blotting, Western Cell Movement Cell Proliferation Cytoskeletal Proteins (metabolism) Female Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Glioblastoma (metabolism, mortality, pathology) Humans Immunoenzyme Techniques Immunoprecipitation Male Middle Aged Neoplasm Grading Neoplasm Invasiveness Phenotype Phosphorylation Prognosis Proto-Oncogene Proteins c-abl (metabolism) Proto-Oncogene Proteins c-crk (metabolism) Signal Transduction Survival Rate Tissue Array Analysis Tumor Cells, Cultured Wound Healing

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