Reciprocal regulation of Abl kinase by Crk Y251 and Abi1 controls invasive phenotypes in glioblastoma
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Sushil Kumar1, Bin Lu2,3, Updesh Dixit1, Sajjad Hossain4, Yongzhang Liu2, Jing Li5, Peter Hornbeck5, Weiming Zheng6, Adam G. Sowalsky7, Leszek Kotula4 and Raymond B. Birge1
1 Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers New Jersey Medical School, Newark, New Jersey, USA
2 Institute of Biophysics, School of Life Sciences, Wenzhou Medical University, Wenzhou, China
3 Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical University, Wenzhou, China
4 Departments of Urology and Biochemistry and Molecular Biology, SUNY Upstate Medical University, New York, NY, USA
5 Cell Signaling Technology, Danvers, MA, USA
6 Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
7 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Raymond B. Birge, email:
Leszek Kotula, email:
Keywords: non-canonical Crk signaling, Abi1, glioblastoma multiformae, cell invasion
Received: September 22, 2015 Accepted: September 29, 2015 Published: October 12, 2015
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.
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