PIKE GTPase Signaling and Function

• Type of Material: Article
• Authors: Jee-Yin Ahn, Emory University; Keqiang Ye, Emory University
• Language: English
• Date: 2005
• Publisher: Ivyspring International Publisher
• Publication Version: Final Published Version
• Copyright Statement: © Ivyspring International Publisher.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 2.0 Generic
• Final Published Version (URL): http://www.ijbs.com/v01p0044.htm
• Title of Journal or Parent Work: International Journal of Biological Sciences
• ISSN: 1449-2288
• Volume: 1
• Issue: 2
• Start Page: 44
• End Page: 50
• Grant/Funding Information: This work is supported by grants from American Cancer Society (#RSG-04-077-01-TBE) and NIH (RO1 NS045627).
• Keywords: PIKEPI; GTPase; ArfGAP; 3-kinase; PLC-γ1; GEF
• Research Categories: Health Sciences, General; Health Sciences, Oncology; Health Sciences, Pathology

Abstract

PIKE (PI 3-Kinase Enhancer) is a recently identified brain specific nuclear GTPase, which binds PI 3-kinase and stimulates its lipid kinase activity. Nerve growth factor treatment leads to PIKE activation by triggering the nuclear translocation of phospholipase C-γ1 (PLC-γ1), which acts as a physiologic guanine nucleotide exchange factor (GEF) for PIKE through its SH3 domain. To date, three forms of PIKE have been characterized: PIKE-S, PIKE-L and PIKE-A. PIKE-S is initially identified shorter isoform. PIKE-L, a longer isoform of PIKE gene, differs from PIKE-S by C-terminal extension containing Arf-GAP (ADP ribosylation factor-GTPase Activating Protein) and two ankyrin repeats domains. In contrast to the exclusive nuclear localization of PIKE-S, PIKE-L occurs in both the nucleus and the cytoplasm. PIKE-L physiologically associates with Homer 1, an mGluR I binding adaptor protein. The Homer/PIKE-L complex couples PI 3-kinase to mGluR I and regulates a major action of group I mGluRs, prevention of neuronal apoptosis. More recently, a third PIKE isoform, PIKE-A was identified in human glioblastoma multiforme brain cancers. Unlike the brain specific PIKE-L and -S isoforms, PIKE-A distributes in various tissues. PIKE-A contains the same domains present in PIKE-L but lacks N-terminal proline-rich domain (PRD), which binds PI 3-kinase and PLC-γ1. Instead, PIKE-A specifically binds to active Akt and upregulates its activity in a GTP-dependent manner, mediating human cancer cell invasion and preventing apoptosis. Thus, PIKE extends its roles from the nucleus to the cytoplasm, mediating cellular processes from cell invasion to programmed cell death.