Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion.
Isoform A of phosphatidylinositol 3-kinase enhancer (PIKE-A) is a newly identified prooncogenic factor that has been implicated in cancer cell growth. How PIKE-A activity is regulated in response to growth signal is poorly understood. Here, we demonstrate that cyclin dependent kinase 5 (Cdk5), a protein known to function mainly in postmitotic neurons, directly phosphorylates PIKE-A at Ser-279 in its GTPase domain in glioblastoma cells. This phosphorylation event stimulates PIKE-A GTPase activity and the activity of its downstream effector Akt. Growth signal activates Cdk5 and results in a Cdk5-dependent accumulation of phosphorylated PIKE-A and activation of Akt in the nucleus. Furthermore, PIKE-A phosphorylation and Cdk5 are increased in human glioblastoma specimens. Phosphorylation of PIKE-A by Cdk5 mediates growth factor-induced migration and invasion of human glioblastoma cells. Together, these findings identify PIKE as the first Cdk5 target in cancer cells, revealing a previously undescribed regulatory mechanism that mediates growth signal-induced activation of PIKE-A/Akt and tumor invasion.
Liu
Ren
R
Departments of Pharmacology, Neurology, and Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Tian
Bo
B
Gearing
Marla
M
Hunter
Stephen
S
Ye
Keqiang
K
Mao
Zixu
Z
D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D002465:Cell Movement; D016543:Central Nervous System Neoplasms / Q000201:enzymology / Q000473:pathology*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012694:Serine / Q000378:metabolism
D020690:GTPase-Activating Proteins; D012694:Serine; D051360:Cyclin-Dependent Kinase 5; D051057:Proto-Oncogene Proteins c-akt; C485997:AGAP2 protein, human; D019204:GTP-Binding Proteins