PIKE GTPase are phosphoinositide-3-kinase enhancers, suppressing programmed cell death Keqiang Ye, Emory University Chi Chan, Emory University Journal Title: Journal of Cellular and Molecular Medicine Volume: Volume 11, Number 1 Publisher: Wiley Open Access | 2007-01-01, Pages 39-53 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.1111/j.1582-4934.2007.00014.x Permanent URL: https://pid.emory.edu/ark:/25593/pq6k3 Final published version: http://dx.doi.org/10.1111/j.1582-4934.2007.00014.x Copyright information: © 2007 The Authors © 2007 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution 3.0 Unported License ( http://creativecommons.org/licenses/by/3.0/), which permits distribution, public display, and publicly performance, distribution of derivative works, making multiple copies, provided the original work is properly cited. This license requires copyright and license notices be kept intact, credit be given to copyright holder and/or author. Accessed October 2, 2021 11:52 AM EDT Apoptosis Review Series J. Cell. Mol. Med. Vol 11, No 1, 2007 pp. 39-53 PIKE GTPase are phosphoinositide-3-kinase enhancers, suppressing programmed cell death Chi Bun Chan, Keqiang Ye * Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA Received: November 29, 2006; Accepted: January 5, 2007 • Introduction • Phosphoinositol lipids as a feedback regulator to • The structure, tissue distribution and cellular PIKE-L activation and translocation localization of PIKEs • Anti-apoptotic activity of PIKE-A in cancers • Mitogenic PIKE-S signaling in the nucleus • PIKE-A as the physiological substrate of Fyn • Anti-apoptotic function of PIKE-L in neurons • Perspective remarks • Role of PIKE-L in merlin inhibited growth suppression Abstract Phosphoinositide-3-kinase enhancers (PIKE) are GTP-binding proteins that posses anti-apoptotic functions. The PIKE family includes three members, PIKE-L, PIKE-S and PIKE-A, which are originated from a single gene (CENTG1) through alternative splicing or differential transcription initiation. Both PIKE-S and PIKE-L bind to phosphoinositide-3-kinase (PI3K) and enhance its activity. PIKE-A does not interplay with PI3K. Instead, it interacts with the downstream effector Akt and promotes its activity. These actions are mediated by their GTPase activity. Because both PI3K and Akt are important effectors in the growth factor-mediated signaling which triggers cellular growth and acts against apoptosis, PIKEs therefore serve as the molecular switch that their activation are crucial for growth factors to exert their physiological functions. In this review, the current understanding of different PIKE isoforms in growth factors-induced anti-apoptotic function will be discussed. Moreover, the role of PIKE in the survival and invasion activity of cancer cells will also be introduced. Keywords: Akt • apoptosis • GTPase • PI3K • PIKE Introduction Nerve growth factor (NGF) is a protein secreted by ways are triggered upon activation of Trk A by NGF and various neuron targets during development in both could be roughly classified into two categories: the peripheral tissues and central nervous system. It is small-GTPase pathway and the phospholipids pathway. an important factor that controls the proliferation, dif- Among all the pathways triggered by activated ferentiation, migration, survival and death of neu- Trk A, the phosphoinositide-3-kinases (PI3K)/Akt ronal cells [1]. This protein exerts its physiological pathway is critical for NGF to maintain neuronal function through binding to its specific receptor cell survival. PI3Ks are lipid kinases that phospho- (Trk A) which is a single-transmembrane receptor rylate phosphatidylinositol (PI) and its deriv- tyrosine kinase [2]. Numerous signal transduction path atives phosphatidylinositol-4-phosphate (PI-4-P) and *Correspondence to: Keqiang YE Tel.: +404 712 2814 Department of Pathology and Laboratory Medicine, E-mail: [email protected] Emory University School of Medicine, Atlanta, GA 30322, USA. doi:10.1111/j.1582-4934.2007.00014.x © 2007 The Authors Journal compilation © 2007 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd phosphatidylinositol-4,5-biphosphate (PI-4,5-P2) to inositid lipids are important in regulating cell prolifer- give phosphatidylinositol-3-phosphate (PI-3-P), ation and differentiation [19, 20]. Nevertheless, the phosphatidylinositol-3,4-biphosphate (PI-3,4-P2) and regulatory mechanisms of PI3K in the nucleus are phosphatidylinositol-3,4,5-triphosphate (PI-3,4,5-P3), not obvious. The identification of phosphoinositide-3- respectively. They are heterodimers composed of a kinase enhancers (PIKE), therefore, represents a catalytic subunit (p110) and a regulatory subunit breakthrough in this area. In this review, characteris- (p85). The kinases are grouped into three classes tics of the three PIKE isoforms as well as their roles (classes I, II and III) based on their sequence in preventing apoptosis will be discussed. Moreover, homologies and substrate preferences [3]. Upon Trk the role of PIKE in the survival and invasion of A activation, classes IA PI3K is recruited to the intra- glioblastomas will also be introduced. cellular tail of Trk A via adaptor proteins like Shc and Gab1 [4,5] where they phosphorylate the PI into var- ious inositol phospholipids. The conversion of PI to The structure, tissue distribution PI-3,4,5-P by class I PI3Ks have been studied most 3 and cellular localization of PIKEs extensively because the PI-3,4,5-P3 is an important intracellular messenger that binds to the pleckstrin homology (PH) domain of a great variety of proteins PIKE proteins are GTP-binding proteins which con- and activates downstream effector molecules for fur- tain three members, PIKE-S, PIKE-L and PIKE-A ther signal conduction. Nowadays, more than hun- (Fig. 1). They are originated from a single gene, dreds of proteins are found to posses the PH CENTG1, by alternative splicing (PIKE-S and PIKE- domains. Akt (protein kinase B) is one of the well- L) or differential transcription start site usage (PIKE- known examples of such PH-containing proteins. Akt A) [21, 22]. PIKE-S contains three praline-rich is a serine/threonine kinase which belongs to the domains (PRD) at the N-terminus, followed by a cAMP-dependant protein kinase A/protein kinase GTP-binding motif (the GTPase region) and a PH G/protein kinase C (AGC) superfamily [6]. The major domain. PIKE-L is the longer isoform of PIKE-S function of Akt is to promote growth factor-mediated which possesses an extra C-terminal extension that cell survival and to block apoptosis via phosphorylat- includes a domain showing sequence homology to ing a great variety of proteins. For example, Akt ARF/GAP protein (Arf-GAP) and two ankyrin repeats phosphorylates proteins in the Bcl-2 and caspases (ANK). PIKE-A shares identical structure with PIKE- families, suppressing apoptosis initiation [7, 8]. It has L at the C-terminal but differ at the N-terminal that also been reported that transcription factors like PIKE-A has no PRD. Forkhead (FoxO) family members and nuclear factor- Although the PIKEs are generated from the same ␬B (NF-␬B) were substrates of Akt which suggested gene, their tissue distribution and cellular localization that Akt could regulate cell survival through interact- are different. Northern blot analysis and immunoblot- ing with the transcription factors that are responsible ting using a specific antibody against the N-terminal for apoptotic gene transcription [9,10]. showed that PIKE-S was found prominently in brain Because the PI3Ks were found predominately in [23]. Moreover, in situ hybridization showed that the cytosol, most attentions were drawn to delineate PIKE-S was expressed exclusively in the neurons of the signal transduction pathway involving the cytoso- cortex, hippocampus and cerebellum. The highest lic PI3Ks. Since the first report by Neri et al. [11] it is level was found in both CA1 region of hippocampus now obvious that the translocation of PI3K from cyto- and the dentate gyrus. Low intensity signal was plasm to nucleus is a common phenomenon in sev- detected in the molecular layer of cerebellum, but enriched in granule and Purkinje cells [23]. Further eral cell types [12–16]. The generation of PI-3,4,5-P3 by PI3K in the nucleus promotes cell survival in a studies using immunofluorescent staining and cellu- transcription-independent manner which inhibits the lar fractionation techniques revealed that PIKE-S caspase-3-activated DNA fragmentation factor/ was nuclear specific [23]. Caspase-activated DNase (DFF40/CAD) [17]. It is Like PIKE-S, PIKE-L is also brain specific. Although PIKE-S and PIKE-L could be found in the also found that nuclear PI-3,4,5-P3 activates nucle- ophosmin/B23 which in turn prevents the apoptotic cortex, hippocampus and olfactory bulb, no PIKE-L DNA fragmentation [18]. In fact, nuclear phiospho- was found in cerebellum as shown in the Western 40 © 2007 The Authors Journal compilation © 2007 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd J. Cell. Mol. Med. Vol 11, No 1, 2007 Fig. 1 Structure of PIKE proteins. Schematic rep- resentations of PIKE proteins (A) and partial alignment of the PH domains of rat PIKEs amino acids (B) were shown. The structure which is different from that of other isoforms in PIKE-A is shown in red. Identical amino acids were marked with an asterisk and the corre- sponding position of the amino acid in each protein was numbered. blot analysis [21]. Using an identical biochemical leucocytes [24–26]. Within the brain region, PIKE-A fractionation techniques as that used in PIKE-S was detected in cerebellum, cerebral cortex, occipital studies, PIKE-L was detected primarily in the nuclear pole, frontal lobe, temporal lobe and putamen [26]. fraction but substantial level was also found in the Similar to PIKE-L, PIKE-A was found both in the cytoplasmic fraction of rat brain homogenates.