PIKE GTPase-mediated nuclear signalings promote cell survival.
The nuclear GTPase PIKE (PI 3-kinase Enhancer) binds PI 3-kinase and enhances it lipid kinase activity. PIKE predominantly distributes in the brain, and nerve growth factor stimulation triggers PIKE activation by provoking nuclear translocation of PLC-gamma1, which acts as a physiologic guanine nucleotide exchange factor (GEF) for PIKE through its SH3 domain. PIKE contains GTPase and ArfGAP domains, which are separated by a PH domain. C-terminal ArfGAP domain activates its internal GTPase activity, and this process is regulated by the interaction between phosphatidylinositols and PH domain. PI 3-kinase occurs in the nuclei of a broad range of cell types, and various stimuli elicit its nuclear translocation. The nuclei from NGF-treated PC12 cells are resistant to DNA fragmentation initiated by activated cell-free apoptosome, for which PIKE/nuclear PI 3-kinase signaling through nuclear PI(3,4,5)P(3) and Akt plays an essential role. As a nuclear receptor for PI(3,4,5)P(3,) B23 binds to PI(3,4,5)P(3) in an NGF-dependent way. The PI(3,4,5)P(3)/B23 complex inhibits DNA fragmentation activity of CAD. Nuclear Akt regulation of apoptosis is dependent on its phosphorylation of key substrates in the nucleus, but the identities of these substrates are unknown. Identification of its nuclear substrates will further our understanding of the physiological roles of nuclear PI 3-kinase/Akt signaling.
Ye
Keqiang
K
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. kye@emory.edu
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism*; D002468:Cell Physiological Phenomena; D002470:Cell Survival / Q000502:physiology*; D005246:Feedback / Q000502:physiology; D006801:Humans; D009685:Nuclear Envelope / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology*
D019869:Phosphatidylinositol 3-Kinases