TY - JOUR
T1 - Reciprocal regulation of Abl kinase by Crk Y251 and Abi1 controls invasive phenotypes in glioblastoma
AU - Kumar, Sushil
AU - Lu, Bin
AU - Dixit, Updesh
AU - Hossain, Sajjad
AU - Liu, Yongzhang
AU - Li, Jing
AU - Hornbeck, Peter
AU - Zheng, Weiming
AU - Sowalsky, Adam G.
AU - Kotula, Leszek
AU - Birge, Raymond B.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Abi1
KW - Cell Invasion
KW - Glioblastoma multiformae
KW - Non canonical Crk signaling
UR - http://www.scopus.com/inward/record.url?scp=84947794538&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84947794538&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.6096
DO - 10.18632/oncotarget.6096
M3 - Article
C2 - 26473374
AN - SCOPUS:84947794538
SN - 1949-2553
VL - 6
SP - 37792
EP - 37807
JO - Oncotarget
JF - Oncotarget
IS - 35
ER -