Identification of a human rasGAP-related protein containing calmodulin-binding motifs.

Weissbach, Lawrence; Settleman, Jeffrey; Kalady, Matthew F.; Snijders, Allard J.; Murthy, Anita E.; Yan, Yaxi; Bernards, André

doi:10.1016/s0021-9258(17)32023-9

Cited by 217 publications

(60 citation statements)

References 31 publications

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“…IQGAP ( IQ —IQ domain; GAP —domain with sequence similarity to the catalytic domain of RasGAPs, also known as GRD, GAP-related domain) proteins are well-established effectors of both mammalian and Dictyostelium Rho GTPases. Initially, they were considered to function as RasGAP proteins, but early experiments demonstrated that they do not bind Ras GTPases or have a RasGAP activity [ 216 , 217 , 218 , 219 , 220 ]. Instead, mammalian IQGAP1 and IQGAP3 interacted with activated Cdc42 and Rac1, with a higher affinity for Cdc42 [ 217 , 218 , 219 , 221 ], while IQGAP2 interacted with these two GTPases without discriminating their GTP- and GDP-bound forms [ 216 , 219 ].…”

Section: Comparative Analysis Of the Rho Signalling In Dictyostelium And Mammalian Cellsmentioning

confidence: 99%

Regulation of the Actin Cytoskeleton via Rho GTPase Signalling in Dictyostelium and Mammalian Cells: A Parallel Slalom

Filić

Mijanović

Putar

et al. 2021

Cells

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Both Dictyostelium amoebae and mammalian cells are endowed with an elaborate actin cytoskeleton that enables them to perform a multitude of tasks essential for survival. Although these organisms diverged more than a billion years ago, their cells share the capability of chemotactic migration, large-scale endocytosis, binary division effected by actomyosin contraction, and various types of adhesions to other cells and to the extracellular environment. The composition and dynamics of the transient actin-based structures that are engaged in these processes are also astonishingly similar in these evolutionary distant organisms. The question arises whether this remarkable resemblance in the cellular motility hardware is accompanied by a similar correspondence in matching software, the signalling networks that govern the assembly of the actin cytoskeleton. Small GTPases from the Rho family play pivotal roles in the control of the actin cytoskeleton dynamics. Indicatively, Dictyostelium matches mammals in the number of these proteins. We give an overview of the Rho signalling pathways that regulate the actin dynamics in Dictyostelium and compare them with similar signalling networks in mammals. We also provide a phylogeny of Rho GTPases in Amoebozoa, which shows a variability of the Rho inventories across different clades found also in Metazoa.

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Section: Comparative Analysis Of the Rho Signalling In Dictyostelium And Mammalian Cellsmentioning

confidence: 99%

Regulation of the Actin Cytoskeleton via Rho GTPase Signalling in Dictyostelium and Mammalian Cells: A Parallel Slalom

Filić

Mijanović

Putar

et al. 2021

Cells

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“…Taken together, the in vivo data suggest that endothelial IQGAP1 is necessary for the development of CNV by interacting with active Rac1. On a molecular level, the GAP-related domain (GRD) of IQGAP1 binds to active Rac1 [73,74], and this interaction maintains Rac1 in its GTP-bound state instead of accelerating the hydrolysis of Rac1GTP to Rac1GDP due to the expression of threonine in place of the catalytic arginine [75,76]. Specifically, choroidal endothelial cells transfected with a GFP-tagged IQGAP1 construct that interfered with Rac1GTP binding IQGAP1 (GFP-IQ-MK24) [77] had reduced ability to sustain Rac1 activation by VEGF compared to choroidal endothelial cells transfected with control GFP-tagged full-length IQGAP1 (GFP-IQ-WT) [32].…”

Section: Iqgapsmentioning

confidence: 99%

Regulation of Rac1 Activation in Choroidal Endothelial Cells: Insights into Mechanisms in Age-Related Macular Degeneration

Ramshekar

Wang

Hartnett

2021

Cells

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Age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide. Vision loss from the neovascular form is associated with the invasion of choroidal endothelial cells into the neural retina to form vision-threatening macular neovascularization (MNV). Anti-angiogenic agents are the current standard of care but are effective in only ~50% of AMD cases. The molecular mechanisms involved in invasive MNV point to the importance of regulating signaling pathways that lead to pathologic biologic outcomes. In studies testing the effects of AMD-related stresses, activation of the Rho GTPase, Rac1, was found to be important for the choroidal endothelial cell invasion into the neural retina. However, current approaches to prevent Rac1 activation are inefficient and less effective. We summarize active Rac1-mediated mechanisms that regulate choroidal endothelial cell migration. Specifically, we discuss our work regarding the role of a multidomain protein, IQ motif containing GTPase activating protein 1 (IQGAP1), in sustaining pathologic Rac1 activation and a mechanism by which active Rap1, a Ras-like GTPase, may prevent active Rac1-mediated choroidal endothelial cell migration.

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“…3 IQGAP1 was first discovered in metastatic osteosarcoma in 1994. 4 For more than 20 years, studies have shown that IQGAP1 is an oncogene and contributes to tumorigenesis. [5][6][7] In a clinical immunohistochemical gastric cancer study, Walch 8 discovered that increased IQGAP1 expression was related to more advanced TNM stages in gastric cancer patients, and patients lacking IQGAP1 expression had a favorable prognosis.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of IQGAP1 inhibits epithelial‐mesenchymal transition via the HIF1α/VEGF‐A signaling pathway in gastric cancer

Liu

et al. 2019

J of Cellular Biochemistry

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As an oncogene, IQ‐domain GTPase‐activating protein 1 (IQGAP1) regulates the epithelial‐mesenchymal transition (EMT) of several cancers, such as breast cancer, thyroid cancer, and esophageal squamous cell carcinoma. However, the role of the scaffold protein IQGAP1 on EMT in gastric cancer remains unclear. Therefore, the present work was performed to address the question. Our results showed that IQGAP1 expression is upregulated in human gastric cancer specimens and cell lines. Furthermore, IQGAP1 knockdown inhibited the migratory ability of gastric cancer cells and reduced the expression of mesenchymal phenotype markers, including Slug, β‐catenin, Snail, Vimentin, and N‐cadherin, as well as vascular endothelial growth factor‐A (VEGF‐A) secretion in gastric cancer cells. Conversely, IQGAP1 downregulation increased the epithelial phenotype marker E‐cadherin. Furthermore, IQGAP1 silencing not only downregulated hypoxia‐inducible transcription factor 1α (HIF1α) but also limited its translocation from the cytosol to the nucleus. Collectively, our results indicated that EMT was regulated by IQGAP1, which was associated with VEGF‐A, since other data demonstrated that HIF1α was involved in VEGF‐A expression. Therefore, we speculated that IQGAP1 regulated EMT of gastric cancer partially via the HIF1α/VEGF‐A signaling pathway. IQGAP1 may serve as an effective therapeutic biomarker for gastric cancer.

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Identification of a human rasGAP-related protein containing calmodulin-binding motifs.

Cited by 217 publications

References 31 publications

Regulation of the Actin Cytoskeleton via Rho GTPase Signalling in Dictyostelium and Mammalian Cells: A Parallel Slalom

Regulation of the Actin Cytoskeleton via Rho GTPase Signalling in Dictyostelium and Mammalian Cells: A Parallel Slalom

Regulation of Rac1 Activation in Choroidal Endothelial Cells: Insights into Mechanisms in Age-Related Macular Degeneration

Downregulation of IQGAP1 inhibits epithelial‐mesenchymal transition via the HIF1α/VEGF‐A signaling pathway in gastric cancer

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