PIKE GTPase signaling and function

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-gamma1 (PLC-gamma1), 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-gamma1. 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.

Figure 1

Diagram of three PIKE isoforms.PIKE-L, an alternatively spliced form of PIKE, which is several hundred amino acids longer than the original form of PIKE, designated as PIKE-S (bankit475414 (AY128689, human)). In addition to the GTPase and PH domains shared by PIKE-S and PIKE-L, PIKE-L contains an ArfGAP domain and two Ankyrin repeats. PIKE-A contains the GTPase, PH, ArfGAP and Ankyrin repeats domains present in PIKE-L but lacks the proline-rich domains (PRD) containing N-terminus, which protein 4.1N, PI 3-kinase and PLC-γ1 bind to.

Figure 2

PLC-γ1/PIKE-S/nuclear PI 3-kinase signalling: NGF treatment of PC12 cells provokes PLC-γ1 nuclear translocation, and stimulates PIKE-S GTPase to bind GTP. The activated PIKE-S binds and elevates nuclear translocated PI 3-kinase activity. NGF also causes 4.1N to translocate to the nucleus over a period of hours, lagging behind the translocation of PI 3-kinase and the peak activation of PIKE elicited by NGF. The decline of activated nuclear PI 3-kinase, which coincides with the appearance of nuclear 4.1N, might involve 4.1N sequestering PIKE away from nuclear PI 3-kinase. The decline of PIKE's NGF-induced GTPase activation takes place at about the same time and so also may participate in the decline of nuclear PI 3-kinase.

Figure 3

PIKE binding proteins: Protein 4.1N and PI 3-kinase share the same binding motif on the N-terminus of PIKE. The third proline-rich domain of PIKE binds SH3 domain of PLC-γ1. mGluR I adaptor protein Homer 1 interacts with PIKE through “Homer binding motif PXPF (a.a. 187-190)”. Akt associates with PIKE-A through its GTPase and C-terminal ankyrin repeats domains.