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Oncotarget. 2015 Nov 10;6(35):37792-807. doi: 10.18632/oncotarget.6096.

Reciprocal regulation of Abl kinase by Crk Y251 and Abi1 controls invasive phenotypes in glioblastoma.

Author information

  • 1Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers New Jersey Medical School, Newark, New Jersey, USA.
  • 2Institute of Biophysics, School of Life Sciences, Wenzhou Medical University, Wenzhou, China.
  • 3Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical University, Wenzhou, China.
  • 4Departments of Urology and Biochemistry and Molecular Biology, SUNY Upstate Medical University, New York, NY, USA.
  • 5Cell Signaling Technology, Danvers, MA, USA.
  • 6Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 7Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

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.

KEYWORDS:

Abi1; cell invasion; glioblastoma multiformae; non-canonical Crk signaling

PMID:
26473374
PMCID:
PMC4741966
DOI:
10.18632/oncotarget.6096
[PubMed - indexed for MEDLINE]
Free PMC Article
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