Scaffolding protein IQGAP1: an insulin-dependent link between caveolae and the cytoskeleton in primary human adipocytes?

Jufvas, Åsa; Rajan, Meenu Rohini; Jönsson, Cecilia; Strålfors, Peter; Turkina, Maria V.

doi:10.1042/bcj20160581

Cited by 10 publications

(10 citation statements)

References 55 publications

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“…Caveolins are a family of integral membrane proteins that constitute the principal components of caveolae membranes and are involved in receptor‐independent endocytosis . The IQGAP1 colocalization with the prescribed caveolae marker protein, caveolin‐1, has been established by confocal microscopy and proximity assay . Yamaga et al (2004) reported that p122RhoGAP/DLC‐1 binds caveolin‐1 through the RhoGAP domain, and that the START domain could bind to cholesterol.…”

Section: Discussionmentioning

confidence: 99%

“…[41][42][43] The IQGAP1 colocalization with the prescribed caveolae marker protein, caveolin-1, has been established by confocal microscopy and proximity assay. 44 Yamaga et al (2004) reported that p122RhoGAP/DLC-1 binds caveolin-1 through the RhoGAP domain, and that the START domain could bind to cholesterol. Furthermore, in PC12 cells, the agonist-induced primary increase in Ca 2+ recruits PLC-δ1 into lipid rafts from other parts of the PM or the CY by other scaffold proteins.…”

Section: Discussionmentioning

confidence: 99%

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IQGAP1 activates PLC‐δ1 by direct binding and moving along microtubule with DLC‐1 to cell surface

et al. 2019

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Phospholipase C (PLC)‐δ1, 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‐δ1 binds to IQGAP1‐N, forming a complex. In fluorescence microscopy, small dots of PLC‐δ1 created fine linear arrays like microtubules, and IQGAP1 and p122RhoGAP/DLC‐1 were colocated in the cytoplasm with PLC‐δ1. Ionomycin induced the raft recruitment of the PLC‐δ1, 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‐δ1 that moves along microtubules and enhances the PLC activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

IQGAP1 activates PLC‐δ1 by direct binding and moving along microtubule with DLC‐1 to cell surface

et al. 2019

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“…Moreover, we and others previously reported that IQGAP1 also interacts with receptor tyrosine kinases including VEGF receptor type 2 in endothelial cells and PDGF receptor in VSMC to couple receptor tyrosine kinases signal to enhance migratory responses (18,50). Of note, IQGAP1 is localized at caveolae/ lipid rafts in primary human adipocytes and VSMCs (14,18).…”

Section: Introductionmentioning

confidence: 63%

Copper transporter ATP7A interacts with IQGAP1, a Rac1 binding scaffolding protein: role in PDGF-induced VSMC migration and vascular remodeling

Ashino

Varadarajan

Ash

et al. 2018

American Journal of Physiology-Cell Physiology

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Vascular smooth muscle cell (VSMC) migration contributes to neointimal formation after vascular injury. We previously demonstrated that copper (Cu) transporter ATP7A is involved in platelet-derived growth factor (PDGF)-induced VSMC migration in a Cu- and Rac1-dependent manner. The underlying mechanism is still unknown. Here we show that ATP7A interacts with IQGAP1, a Rac1 and receptor tyrosine kinase binding scaffolding proteins, which mediates PDGF-induced VSMC migration and vascular remodeling. In cultured rat aortic SMCs, PDGF stimulation rapidly promoted ATP7A association with IQGAP1 and Rac1 and their translocation to the lipid rafts and leading edge. Cotransfection assay revealed that ATP7A directly bound to NH2-terminal domain of IQGAP1. Functionally, either ATP7A or IQGAP1 depletion using siRNA significantly inhibited PDGF-induced VSMC migration without additive effects, suggesting that IQGAP1 and ATP7A are in the same axis to promote migration. Furthermore, IQGAP1 siRNA blocked PDGF-induced ATP7A association with Rac1 as well as its translocation to leading edge, while PDGF-induced IQGAP1 translocation was not affected by ATP7A siRNA or Cu chelator. Overexpression of mutant IQGAP1 lacking a Rac1 binding site prevented PDGF-induced translocation of Rac1, but not ATP7A, to the leading edge, thereby inhibiting lamellipodia formation and VSMC migration. In vivo, ATP7A colocalized with IQGAP1 at neointimal VSMCs in a mice wire injury model, while neointimal formation and extracellular matrix deposition induced by vascular injury were inhibited in ATP7A mutant mice with reduced Cu transporter function. In summary, IQGAP1 functions as ATP7A and Rac1 binding scaffolding protein to organize PDGF-dependent ATP7A translocation to the lamellipodial leading edge, thereby promoting VSMC migration and vascular remodeling.

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“…Caveolins are a family of integral membrane proteins that constitute the principal components of caveolae membranes and are involved in receptor-independent endocytosis (Scherer et al, 1996, Tang et al, 1996, Williams et al, 2004). The IQGAP1 colocalization with the prescribed caveolae marker protein, caveolin-1, has been established by confocal microscopy and proximity assay (Jufvas et al, 2016). Yamaga et al (2004) reported that p122RhoGAP/DLC-1 binds caveolin-1 through the RhoGAP domain, and that the START domain could bind to cholesterol.…”

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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Scaffolding protein IQGAP1: an insulin-dependent link between caveolae and the cytoskeleton in primary human adipocytes?

Cited by 10 publications

References 55 publications

IQGAP1 activates PLC‐δ1 by direct binding and moving along microtubule with DLC‐1 to cell surface

IQGAP1 activates PLC‐δ1 by direct binding and moving along microtubule with DLC‐1 to cell surface

Copper transporter ATP7A interacts with IQGAP1, a Rac1 binding scaffolding protein: role in PDGF-induced VSMC migration and vascular remodeling

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

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