PIKE (phosphatidylinositol 3-kinase enhancer)-A GTPase stimulates Akt activity and mediates cellular invasion.
Akt/PKB is a crucial regulator of diverse cellular processes and contributes to cancer progression. Activation of Akt is essentially dependent on phosphatidylinositol (PI) 3-kinase signaling. Here, we describe a novel mediator of Akt that is independent of PI 3-kinase. This mediator, PIKE-A, is a PIKE isoform and contains GTPase, pleckstrin homology, ArfGAP, and ankyrin repeats domains. PIKE-A directly binds to activated Akt but not PI 3-kinase in a guanine nucleotide-dependent way and stimulates the kinase activity of Akt. Overexpression of PIKE-A enhances Akt activity and promotes cancer cell invasion, whereas dominant-negative PIKE-A and PIKE-A knockdown markedly inhibit these processes. Our results demonstrate that PIKE-A is a physiologic regulator of Akt and an oncogenic effector of cell invasion.
Ahn
Jee-Yin
JY
Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Rong
Rong
R
Kroll
Todd G
TG
Van Meir
Erwin G
EG
Snyder
Solomon H
SH
Ye
Keqiang
K
D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000235:genetics; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000502:physiology; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000502:physiology; D006004:Glycogen Debranching Enzyme System / Q000235:genetics; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction
D020690:GTPase-Activating Proteins; D006004:Glycogen Debranching Enzyme System; D011518:Proto-Oncogene Proteins; C020569:4 alpha-glucanotransferase; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C485997:AGAP2 protein, human; D019204:GTP-Binding Proteins