Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion.

Abstract

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.

• Authors: Ren Liu, Bo Tian, Marla Gearing, Stephen Hunter, Keqiang Ye, Zixu Mao
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 21 Pg. 7570-5 (May 27 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18487454 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• GTPase-Activating Proteins
• Serine
• Cyclin-Dependent Kinase 5
• Proto-Oncogene Proteins c-akt
• AGAP2 protein, human
• GTP-Binding Proteins

Topics

• Active Transport, Cell Nucleus
• Cell Line, Tumor
• Cell Movement
• Central Nervous System Neoplasms (enzymology, pathology)
• Cyclin-Dependent Kinase 5 (metabolism)
• GTP-Binding Proteins (metabolism)
• GTPase-Activating Proteins (metabolism)
• Glioblastoma (enzymology, pathology)
• Humans
• Neoplasm Invasiveness
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Serine (metabolism)