IQGAP1 is a phosphoinositide effector and kinase scaffold

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Abstract

Phosphatidylinositol 4,5-bisphosphate (PI4,5P2) is a lipid messenger that regulates a wide variety of cellular functions. The majority of cellular PI4,5P2 is generated by isoforms of the type I phosphatidylinositol phosphate kinases (PIPKI) that are generated from three genes, and each PIPKI isoform has a unique distribution and function in cells. It has been shown that the signaling specificity of PI4,5P2 can be determined by a physical association of PIPKs with PI4,5P2 effectors. IQGAP1 is newly identified as an interactor of multiple isoforms of PIPKs. Considering the versatile roles of IQGAP1 in cellular signaling pathways, IQGAP1 may confer isoform-specific roles of PIPKs in distinct cellular locations. In this mini review, the emerging roles of PIPKs that are regulated by an association with IQGAP1 will be summarized. Focuses will be on cell migration, vesicle trafficking, cell signaling, and nuclear events.

Introduction

Phosphoinositides (phosphorylated phosphatidylinositol (PI) at the 3, 4 and 5 hydroxyl) are key lipid messengers regulating almost every aspect of eukaryotic cell physiology (Lemmon, 2008). Among the 7 isomers, PI 4,5-bisphosphate (PI4,5P2) has a central role in generating other phosphoinositide species and other lipid messengers (Balla, 2013, Di Paolo and De Camilli, 2006). Also, PI4,5P2 directly interacts with vast array of proteins called PI4,5P2 effectors and regulates their functions in the vicinity of various cellular membranes and in the nucleus (Choi et al., 2015, Irvine, 2003, Yin and Janmey, 2003). In most eukaryotic cells, PI4,5P2 is present at a higher concentration than other phosphoinositide isomers, and its overall concentration largely remains unchanged in response to extracellular stimuli (Insall and Weiner, 2001, Lemmon, 2008), recapitulating its housekeeping role in cellular physiology. However, its local concentration at a specific time and location is dramatically altered by the stimuli in order to efficiently regulate stimuli-directed functions. For example, in response to chemokines, PI4,5P2 and PI3,4,5P3 accumulate at the leading edges of migrating cells and regulate targeting and activity of numerous cytoskeleton regulatory proteins (Choi et al., 2013, Franca-Koh et al., 2007).

Changes in local PI4,5P2 concentration are controlled by redistribution and activation of PI4,5P2 generating enzymes in response to the stimuli (Balla, 2013, Divecha, 2010). In higher eukaryotes, the majority of PI4,5P2 is generated by type I and II phosphatidylinositol phosphate kinases (PIPKIs and PIPKIIs) by phosphorylating PI4P and PI5P, respectively (Heck et al., 2007). For both PIPKI and PIPKII there are three genes, (α, β and γ) and splice variants are found in higher eukaryotes (van den Bout and Divecha, 2009). Advances in the phosphoinositide signaling have revealed that many PI4,5P2 effectors are physically associated with PI4,5P2 generating enzymes and the association is closely regulated by the stimuli. In this mechanism, PI4,5P2 generation is tightly linked to effector activation. We and others have discovered PI4,5P2 effectors whose functions are directly regulated by association with PIPKI and PIPKII isoforms. These include actin regulatory proteins, regulators of membrane trafficking, enzymes, adaptors and transcription factors (Barlow et al., 2012, Choi et al., 2015, Ling et al., 2006, Shah et al., 2013).

Recently, the scaffold protein IQ motif containing GTPase activating protein 1 (IQGAP1) has been shown to bind phosphoinositides and to multiple PIPKI and PIPKII members (Choi et al., 2013). Interestingly, the functions that are regulated by IQGAP1 or the PIPKI and PIPKII isoforms often overlap, and they also share many common binding partners (Choi et al., 2015, Hedman et al., 2015). This suggests that IQGAP1 is a key regulator of phosphoinositide signaling. In this mini review, we will summarize the cellular functions of PIPKI and PIPKII isoforms that are regulated by IQGAP1 and how phosphoinositides may regulate IQGAPs.

Section snippets

Phosphatidylinositol phosphate kinase interaction with IQGAP1

The phosphatidylinositol phosphate kinase (PIPKs) family is distinct from other lipid kinases and protein kinases as no significant homology is found (Boronenkov et al., 1998, Heck et al., 2007, Sasaki et al., 2009). Based on sequence homology, domain structure and substrate preference, PIPKs can be classified into three distinct types (type I, II and III). In vivo, type I and II enzymes generate PI4,5P2 by phosphorylating PI4P and PI5P, respectively. Type III enzymes preferentially use PI3P as

IQGAP1 interaction with PIPKIγ regulates cell motility

In vitro, IQGAP1 binds to PIPKIγ with a moderate binding affinity (Choi et al., 2013). The binding is increased by stimuli for cell migration such as growth factors and ECM, suggesting their roles in cell migration. Biochemical and cell biological analyses revealed that PIPKIγ and IQGAP1 association with membrane fraction are increased in migrating cells (Choi et al., 2013). As the product of PIPKI, PI4,5P2, is a key mediator of cytoskeleton regulator protein binding to membrane, one could

IQGAP1 interaction with PIPKIγ regulates phosphoinositide signaling

PIPKIs generate PI4,5P2 and PI4,5P2 can be further phosphorylated by class I phosphoinositide 3-kinases (PI3Ks) to generate PI3,4,5P3. Several key signaling proteins such as phosphoinositide-dependent kinase 1(PDK1) and Akt have PI3,4,5P3 binding modules and PI3,4,5P3 binding regulates their activities and targeting to membranes (Fayard et al., 2005). As expected, PIPKI isoforms are required for Akt activation. In Dictyostelium, depletion of a PIPKI isoform reduces approximately 90% of PI4,5P2

Could IQGAP1 and PIP kinases regulate nuclear signaling?

Four isoforms of PIPKs are shown to localize in the nucleus (PIPKIα, PIPKIγi4, PIPKIIα and PIPKIIβ) and all of these isoforms potentially interact with IQGAP1 (Barlow et al., 2012, Choi et al., 2013, Shah et al., 2013). Consistently, roles of IQGAP1 in the nucleus are emerging. IQGAP1 accumulates in the nucleus in early S phase and regulates cell cycle progression from S to G2/M phase (Johnson et al., 2011). Also, IQGAP1 interacts with many modulators of Wnt signaling pathway and, importantly,

IQGAP1 and IQGAP2 function differently in regulation of cell signaling

IQGAP2 is homologous to IQGAP1. At the amino acid sequence level, IQGAP2 is 62% identical to IQGAP1. Furthermore, IQGAP2 has five domains that are also found in IQGAP1 with varying identity to IQGAP1 (Fig. 2). However, these two similar proteins function oppositely in cells. IQGAP1 is implicated in many human cancers, and its oncogenic functions are validated in diverse cancer models, whereas IQGAP2 functions unequivocally as a tumor suppressor in multiple studies (Brown and Sacks, 2006, Hedman

Summary and future prospects

PIPKs generate a lipid messenger PI4,5P2, and PI4,5P2 signaling specificity is determined by PIPK association with PI4,5P2 effectors (Choi et al., 2015). IQGAP1 interacts with multiple PIPK isoforms and itself is PI4,5P2 effector in regulation of cell migration (Choi et al., 2013). IQGAP1 assembles with PIPKs in various cellular locations to regulate other cellular processes by association with other PI4,5P2 effectors. This suggests that IQGAP1 functions as a signaling platform in regulation of

Acknowledgments

Due to space constraints some relevant studies may not have been referenced. This work was supported by NIH (grant number GM057549) grants to RAA and American Heart Association (grant number 13PRE14690057) fellowships to SC. The authors have declared no conflict of interest.

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