And Akt‐ion! <scp>IQGAP</scp>1 in control of signaling pathways

Choi, Sungyeol; Anderson, Richard A.

doi:10.15252/embj.201796827

Cited by 15 publications

(14 citation statements)

References 11 publications

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“…NKG2D stimulation results in the activation of critical signaling pathways that lead to cytokine gene transcription in NK cells ( 3 ). IQGAP1 regulates multiple kinase signaling programs known to be activated in response to NKG2D ligation, including Erk1/2 and Akt ( 14 , 65 ). Therefore, we examined the requirement of IQGAP1 in NKG2D-mediated signaling in the context of cytokine production.…”

Section: Resultsmentioning

confidence: 99%

“…IQ domain-containing GTPase-activating protein 1 is a ubiquitously expressed, 190-kDa scaffold protein ( 13 ) that regulates cellular signaling in multiple contexts ( 9 , 14 , 15 ). The scaffold function of IQGAP1 is mediated through six functional domains that facilitate its interaction with various proteins and signaling molecules.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, IQGAP1 has been shown to regulate cytoskeletal reorganization ( 16 , 17 ) as well as multiple signaling pathways activated downstream of receptor tyrosine kinases and G protein-coupled receptors. These include estrogen receptor ( 18 ), calmodulin ( 19 ) MAPK ( 20 ), Akt ( 14 , 21 ), mechanistic target of rapamycin (mTOR) ( 22 ), and phosphoinositide ( 23 ) signaling pathways. Interestingly, the role of IQGAP1 can differ based on physiological context.…”

Section: Introductionmentioning

confidence: 99%

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IQ Domain-Containing GTPase-Activating Protein 1 Regulates Cytoskeletal Reorganization and Facilitates NKG2D-Mediated Mechanistic Target of Rapamycin Complex 1 Activation and Cytokine Gene Translation in Natural Killer Cells

et al. 2018

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Natural killer (NK) cells are innate lymphocytes that play essential roles in mediating antitumor immunity. NK cells respond to various inflammatory stimuli including cytokines and stress-induced cellular ligands which activate germline-encoded activation receptors (NKRs), such as NKG2D. The signaling molecules activated downstream of NKRs are well defined; however, the mechanisms that regulate these pathways are not fully understood. IQ domain-containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffold protein. It regulates diverse cellular signaling programs in various physiological contexts, including immune cell activation and function. Therefore, we sought to investigate the role of IQGAP1 in NK cells. Development and maturation of NK cells from mice lacking IQGAP1 (Iqgap1−/−) were mostly intact; however, the absolute number of splenic NK cells was significantly reduced. Phenotypic and functional characterization revealed a significant reduction in the egression of NK cells from the bone marrow of Iqagp1−/− mice altering their peripheral homeostasis. Lack of IQGAP1 resulted in reduced NK cell motility and their ability to mediate antitumor immunity in vivo. Activation of Iqgap1−/− NK cells via NKRs, including NKG2D, resulted in significantly reduced levels of inflammatory cytokines compared with wild-type (WT). This reduction in Iqgap1−/− NK cells is neither due to an impaired membrane proximal signaling nor a defect in gene transcription. The levels of Ifng transcripts were comparable between WT and Iqgap1−/−, suggesting that IQGAP1-dependent regulation of cytokine production is regulated by a post-transcriptional mechanism. To this end, Iqgap1−/− NK cells failed to fully induce S6 phosphorylation and showed significantly reduced protein translation following NKG2D-mediated activation, revealing a previously undefined regulatory function of IQGAP1 via the mechanistic target of rapamycin complex 1. Together, these results implicate IQGAP1 as an essential scaffold for NK cell homeostasis and function and provide novel mechanistic insights to the post-transcriptional regulation of inflammatory cytokine production.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IQ Domain-Containing GTPase-Activating Protein 1 Regulates Cytoskeletal Reorganization and Facilitates NKG2D-Mediated Mechanistic Target of Rapamycin Complex 1 Activation and Cytokine Gene Translation in Natural Killer Cells

et al. 2018

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“…Scaffold proteins for the mitogen-activated protein kinase (MAPK) cascade were among the first to be discovered (Printen et al, 1994, Therrien et al, 1996). The expanding group of MAPK scaffolds comprises several scaffolds for the extracellular signal-regulated kinase (ERK) pathway (Choi et al, 2017), such as kinase suppressor of Ras 1 (KSR1), paxillin, MEK partner 1 (MP1), caveolin-1, and IQGAP1 (Kolch, 2005, Wortzel et al, 2011). Reported target proteins of IQGAP1 are actin, Ca 2+ /calmodulin, E-cadherin, epidermal growth factor receptor, B-Raf, MAPK/ERK kinase1/2, ERK2, and Cdc42 (Pan et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Colocalization of IQGAP1 with DLC-1 and PLC-δ1; Its potential role in coronary spasm

Tanaka

Tomita

Hanada

et al. 2019

Preprint

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Phospholipase C (PLC)-1, activated by p122RhoGTPase-activating protein (GAP)/deleted in liver cancer-1 (p122RhoGAP/DLC-1), contributes to the coronary spastic angina (CSA) pathogenesis. The present study aims to further investigate the p122RhoGAP/DLC-1 protein. We examined molecules assisting this protein and identified a scaffold protein-IQ motif-containing GTPase-activating protein 1 (IQGAP1). IQGAP1-C binds to the steroidogenic acute regulatory-related lipid transfer (START) domain of p122RhoGAP/DLC-1, and PLC-1 binds to IQGAP1-N, forming a complex. In fluorescence microscopy, small dots of PLC-1 created fine linear arrays like microtubules, and IQGAP1 and p122RhoGAP/DLC-1 were colocated in the cytoplasm with PLC-1. Ionomycin induced the raft recruitment of the PLC-1, IQGAP1, and p122RhoGAP/DLC-1 complex by translocation to the plasma membrane (PM), indicating the movement of this complex is along microtubules with the motor protein kinesin. Moreover, the IQGAP1 protein was elevated in skin fibroblasts obtained from patients with CSA, and it enhanced the PLC activity and peak intracellular calcium concentration in response to acetylcholine. IQGAP1, a novel stimulating protein, forms a complex with p122RhoGAP/DLC-1 and PLC-1 that moves along microtubules and enhances the PLC activity.Keywords: Phospholipase C, p122RhoGTPase-activating protein (GAP)/deleted in liver cancer-1, IQ motif-containing GTPase-activating protein 1, coronary spastic angina, acetylcholine (IP 3 ) and diacylglycerol. IP 3 mobilizes Ca 2+ from the intracellular stores and exhibits rapid contraction of the vascular smooth muscle (Korn et al., 1988), whereas diacylglycerol activates protein kinase C and triggers the sustained muscle contraction via a Ca 2+ -independent mechanism (Ito et al., 1994). Previously, we have reported the enhanced PLC activity in cultured skin fibroblasts obtained from patients with CSA and determined that a major PLC isozyme in the membrane fraction was the 1 isoform, which is more sensitive to Ca 2+ than other isozymes (Okumura et al., 2000). Furthermore, we have demonstrated the presence of a G to A mutation at nucleotide position 864 in PLC-1 in patients with CSA, accompanied by the amino acid (aa) replacement of arginine 257 to histidine (R257H), which markedly enhanced the PLC enzymatic activity in the physiological range of the intracellular free calcium concentration ([Ca 2+ ] i ) (Nakano et al., 2002). To elucidate its role in coronary spasm, we created mice that overexpressed the variant PLC-1 (R257H) under the control of the mouse -SMA promoter and illustrated that the elevated PLC-1 activity enhanced coronary vasomotility, as observed in patients with CSA (Shibutani et al., 2012).A study has demonstrated that p122RhoGTPase-activating protein (GAP)/deleted in liver cancer-1 (p122RhoGAP/DLC-1), cloned as a PLC-1-interacting protein from a rat brain expression library, exhibits a specific GTPase-activating protein (GAP) activity on Rho, augmenting the PIP 2 hydrolyzing activity of PLC-1 in vitro...

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“…The domains in IQGAP1 are, starting from the N-terminus, the calponin homology domain (CHD), the poly-proline protein-protein domain (WW), the 4 IQ domains and the RasGAP-related domain (GRD) (Figure 1a). In cells, IQGAP1 functions as a scaffold protein, playing a key role in both the PI3K-Akt and Ras-ERK pathways 8 . Crucial components of these pathways are assembled by IQGAP1.…”

Section: Introductionmentioning

confidence: 99%

The Specificity of IQGAP1 Toward the PI3K-Akt Pathway is Dependent on the IQ3 motif

Chen

Wen

Choi

et al. 2018

Preprint

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Epidermal growth factor receptor (EGFR) and its downstream phosphatidylinositol 3-kinase (PI3K) pathway are commonly deregulated in many cancers including head and neck cancer (HNC). Recently, we have shown that the IQ motif-containing GTPaseactivating protein 1 (IQGAP1) provides a molecular platform to scaffold all the components from the PI3K-Akt pathway and results in the sequential generation of 4,4,5P 3 ). This makes the IQGAP1-PI3K scaffold a promising therapeutic target. In addition to the PI3K-Akt pathway, IQGAP1 also scaffolds the Ras-ERK pathway. To identify an IQGAP1 mutant that specifically loses IQGAP1-PI3K signaling but not other functions, we have focused on the IQ3 motif since this region binds with both the PIPK1a and PI3K enzymes and a short peptide derived from this sequence blocks binding and PI3K signaling. An IQ3 deletion mutant (∆IQ3) in IQGAP1 was functionally compared with wild-type (WT) IQGAP1. We found that the IQ3 domain specifically mediates the PI3K-Akt pathway but does not regulate the Ras-ERK pathway. The IQ3 deletion mutant lost interactions with PI3K-Akt components but retained its binding of ERK pathway components and cell surface receptors, EGFR and integrins. In addition, the IQ3 deletion mutant lost regulation of cell migration. Consistently, the IQ3 motif derived peptide blocked Akt activation and led to the blockage of invasion mediated by EGFR organized into an integrin complex by syndecan-4. Taken together, this work has defined the IQGAP1 IQ3 motif as a specific target sequence for the scaffolding of the PI3K-AKT pathway.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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And Akt‐ion! IQGAP1 in control of signaling pathways

Cited by 15 publications

References 11 publications

IQ Domain-Containing GTPase-Activating Protein 1 Regulates Cytoskeletal Reorganization and Facilitates NKG2D-Mediated Mechanistic Target of Rapamycin Complex 1 Activation and Cytokine Gene Translation in Natural Killer Cells

IQ Domain-Containing GTPase-Activating Protein 1 Regulates Cytoskeletal Reorganization and Facilitates NKG2D-Mediated Mechanistic Target of Rapamycin Complex 1 Activation and Cytokine Gene Translation in Natural Killer Cells

Colocalization of IQGAP1 with DLC-1 and PLC-δ1; Its potential role in coronary spasm

The Specificity of IQGAP1 Toward the PI3K-Akt Pathway is Dependent on the IQ3 motif

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