Identification of a Putative Effector for Cdc42Hs with High Sequence Similarity to the RasGAP-related Protein IQGAP1 and a Cdc42Hs Binding Partner with Similarity to IQGAP2

McCallum, Sandra J.; Wu, Wen Jin; Cerione, Richard A.

doi:10.1074/jbc.271.36.21732

Cited by 146 publications

(193 citation statements)

References 38 publications

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“…Mammalian IQGAP1 was also identified as a CDC42 target, acting through its C-terminal domain (Brill et al, 1996;Kinoshita et al, 1997;McCallum et al, 1996;Kuroda et al, 1996), and the domain structure of yeast and mammalian IQGAPs is conserved (Epp and Chant, 1997;Lippincott and Li, 1998;Osman and Cerione, 1998), implying a conserved function. IQGAP1 is a member of a three-isoform family of proteins that also includes IQGAP2 (Yamashiro et al, 2003) and IQGAP3 .…”

Section: Introductionmentioning

confidence: 99%

A dual role for IQGAP1 in regulating exocytosis

Rittmeyer

Daniel

Hsu

et al. 2008

Journal of Cell Science

173

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Polarized secretion is a tightly regulated event generated by conserved, asymmetrically localized multiprotein complexes, and the mechanism(s) underlying its temporal and spatial regulation are only beginning to emerge. Although yeast Iqg1p has been identified as a positional marker linking polarity and exocytosis cues, studies on its mammalian counterpart, IQGAP1, have focused on its role in organizing cytoskeletal architecture, for which the underlying mechanism is unclear. Here, we report that IQGAP1 associates and co-localizes with the exocyst-septin complex, and influences the localization of the exocyst and the organization of septin. We further show that activation of CDC42 GTPase abolishes this association and inhibits secretion in pancreatic β-cells. Whereas the N-terminus of IQGAP1 binds the exocyst-septin complex, enhances secretion and abrogates the inhibition caused by CDC42 or the depletion of IQGAP1, the C-terminus, which binds CDC42, inhibits secretion. Pulse-chase experiments indicate that IQGAP1 influences protein-synthesis rates, thus regulating exocytosis. We propose and discuss a model in which IQGAP1 serves as a conformational switch to regulate exocytosis.

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Section: Introductionmentioning

confidence: 99%

A dual role for IQGAP1 in regulating exocytosis

Rittmeyer

Daniel

Hsu

et al. 2008

Journal of Cell Science

173

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“…Several proteins that are structurally related to IQGAP1 have been described. The most similar proteins in terms of primary sequence and domain organization are IQGAP2, a liver-enriched protein in mammals (3,10), and a Hydra protein that has been implicated in tentacle formation (11). Additional IQGAP1-related proteins have been found in Dictyostelium (12)(13)(14), and Saccharomyces cerevisiae (15)(16)(17).…”

mentioning

confidence: 99%

“…Analysis of its predicted amino acid sequence revealed that the IQGAP1 polypeptide does contain a GAP-related domain, as well as four putative calmodulin-binding IQ motifs (1). Although the GAP-related domain of IQGAP1 does not seem to have GAP catalytic activity (1,2), it does form part of a region that preferentially binds to activated forms of the small G proteins, Cdc42 and Rac1 (2)(3)(4). IQGAP1 consists of two identical 190-kDa subunits that associate with cortical actin filaments in cultured mammalian cells and cross-links actin filaments into bundles and gels in vitro (2,(5)(6)(7).…”

mentioning

confidence: 99%

The Mechanism for Regulation of the F-actin Binding Activity of IQGAP1 by Calcium/Calmodulin

Mateer

McDaniel²,

Nicolas

et al. 2002

Journal of Biological Chemistry

107

150

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IQGAP1 colocalizes with actin filaments in the cell cortex and binds in vitro to F-actin and several signaling proteins, including calmodulin, Cdc42, Rac1, and ␤-catenin. It is thought that the F-actin binding activity of IQGAP1 is regulated by its reversible association with these signaling molecules, but the mechanisms have remained obscure. Here we describe the regulatory mechanism for calmodulin. Purified adrenal IQGAP1 was found to consist of two distinct protein pools, one of which bound F-actin and lacked calmodulin, and the other of which did not bind F-actin but was tightly associated with calmodulin. Based on this finding we hypothesized that calmodulin negatively regulates binding of IQGAP1 to F-actin. This hypothesis was tested in vitro using recombinant wild type and mutated IQGAP1s and in live cells that transiently expressed IQGAP1-YFP. In vitro, the affinity of wild type IQGAP1 for F-actin decreased with increasing concentrations of calmodulin, and this effect was dramatically enhanced by Ca 2؉ and required the IQ domains of IQGAP1. In addition, we found that calmodulin bound wild type IQGAP1 much more efficiently in the presence of Ca Actin filament organization in the cell is regulated by a diverse set of factors that collectively control actin polymerization, actin filament length, interfilament cross-links, and interactions of polymerized actin with other cytoskeletal systems and membranes. One such regulatory factor,

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“…Like IQGAP1, IQGAP2 binds to Cdc42 in its GTP-bound state and inhibits intrinsic and RhoGAP-stimulated GTP hydrolysis [although the nucleotide dependence of the interaction between IQGAP2 and Cdc42 is not as well established as for IQGAP1 (5,25,33,34)]. Recently, IQGAP2 was proposed to be a Cdc42-dependent regulator of parietal cell HCl secretion (46).…”

mentioning

confidence: 99%

IQGAPs are differentially expressed and regulated in polarized gastric epithelial cells

Chew

Okamoto²,

Chen³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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. IQGAPs are differentially expressed and regulated in polarized gastric epithelial cells. Am J Physiol Gastrointest Liver Physiol 288: G376 -G387, 2005. First published September 30, 2004; doi:10.1152/ajpgi.00290.2004.-IQGAPs, GTPase-activating proteins with an IQ motif, are thought to regulate many actin cytoskeleton-based activities through interactions with Cdc42 and Rac. Recently, Cdc42 was implicated in regulation of gastric parietal cell HCl secretion, and IQGAP2 was immunolocalized with Cdc42 to F-actin-rich intracellular canalicular membranes of isolated gastric parietal cells in primary culture. Here we sought to define distribution and localization of IQGAP1 and IQGAP2 in major oxyntic (acid-secreting) gastric mucosal cell types and to determine whether secretory agonists modulate these proteins. Differential staining protocols were used to identify different cell populations (parietal, chief, surface/pit, and mucous neck cells) in semi-intact glands isolated from rabbit gastric mucosae and to characterize these same cells after dispersion and fractionation on isopycnic density gradients with simultaneous staining for F-actin, H ϩ -K ϩ -ATPase, and GSII lectinbinding sites. There was a pronounced increase in intracellular F-actin staining in dispersed chief cells, apparently from internalization of F-actin-rich apical membranes that normally abut the gland lumen. Therefore, other membrane-associated proteins might also be redistributed by disruption of cell-cell contacts. Western blot analyses were used to quantitate relative concentrations of IQGAPs in defined mucosal cell fractions, and gastric glands were used for in situ localizations. We detected uniform levels of IQGAP2 expression in oxyntic mucosal cells with predominant targeting to regions of cellcell contact and nuclei of all cell types. IQGAP2 was not detected in parietal cell intracellular canaliculi. IQGAP1 expression was variable and targeted predominantly to the cortex of chief and mucous neck cells. Parietal cells expressed little or no IQGAP1 vs. other mucosal cell types. Phosphoprotein affinity chromatography, isoelectric focusing, and phosphorylation site analyses indicated that both IQGAP1 and IQGAP2 are phosphoproteins potentially regulated by [Ca 2ϩ ]i/ PKC and cAMP signaling pathways, respectively. Stimulation of glands with carbachol, which elevates [Ca 2ϩ ]i and activates PKC, induced apparent translocation of IQGAP1, but not IQGAP2, to apical poles of chief (zymogen) and mucous neck cells. This response was mimicked by PMA but not by ionomycin or by elevation of [cAMP] i with forskolin. Our observations support a novel, PKC-dependent role for IQGAP1 in regulated exocytosis and suggest that IQGAP2 may play a more general role in regulating cell-cell interactions and possibly migration within the gastric mucosa. parietal cell; chief cell; protein kinase C; carbachol; actin THE RHO GTPASES Cdc42 and Rac1 regulate actin cytoskeletal dynamics by interacting with a number of effectors, including the IQGAPs (5, 15, 43), which are s...

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Identification of a Putative Effector for Cdc42Hs with High Sequence Similarity to the RasGAP-related Protein IQGAP1 and a Cdc42Hs Binding Partner with Similarity to IQGAP2

Cited by 146 publications

References 38 publications

A dual role for IQGAP1 in regulating exocytosis

A dual role for IQGAP1 in regulating exocytosis

The Mechanism for Regulation of the F-actin Binding Activity of IQGAP1 by Calcium/Calmodulin

IQGAPs are differentially expressed and regulated in polarized gastric epithelial cells

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