Distinct but Overlapping Functions for the Closely Related p190 RhoGAPs in Neural Development

Matheson, Stephen; Hu, Kang‐Quan; Brouns, Madeleine R.; Sordella, Raffaella; VanderHeide, John D.; Settleman, Jeffrey

doi:10.1159/000095116

Cited by 27 publications

(31 citation statements)

References 66 publications

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“…Although it is possible that p190RhoGAP-B regulates these two events independently, at this stage, we cannot exclude that MT1-MMP regulation impacts on podosome induction in response to VEGF-A. p190RhoGAP-B is known to be primarily regulated by subcellular localisation (Matheson et al, 2006) and to regulate the spatial regulation of RhoA activity (Ponik et al, 2013). In VEGF-Astimulated HMVECs, we show that the local activation of RhoA at podosomes was dependent on p190RhoGAP-B.…”

Section: Discussionmentioning

confidence: 70%

VEGF-A stimulates podosome-mediated collagen-IV proteolysis in microvascular endothelial cells

Daubon

Spuul

Alonso

et al. 2016

Journal of Cell Science

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Podosomes are dynamic cell-matrix contact structures that combine several key abilities, including adhesion, matrix degradation and mechanosensing. These actin-based cytoskeletal structures are well known in monocytic cells, but much less is known about those formed in other lineages. In this study, we characterize podosomes in capillary-derived microvascular endothelial cells. We identify two types of podosomes: constitutive podosomes that form in the absence of specific stimulation and induced podosomes that arise in response to the angiogenic factor VEGF-A. Constitutive and VEGF-A-induced podosomes share similar components but exhibit marked differences in terms of gelatinolytic activity. We also show that extracellular matrix proteins are key determinants of the VEGF-A response: laminin and collagen-IV, but neither collagen-I nor fibronectin are conducive for podosome induction. Moreover, only collagen-IV elicits the formation of proteolytically active podosomes through a mechanism involving increased Src phosphorylation, p190RhoGAP-B relocalisation and MT1-MMP cell surface exposure at podosome sites. We hypothesise that by promoting podosome formation, VEGF-A enables endothelial cells to overcome the basement membrane barrier for sprouting away from the existing vasculature.

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Section: Discussionmentioning

confidence: 70%

VEGF-A stimulates podosome-mediated collagen-IV proteolysis in microvascular endothelial cells

Daubon

Spuul

Alonso

et al. 2016

Journal of Cell Science

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“…p190A was first described as a tyrosine-phosphorylated protein in a complex with p120 RasGAP in serum-stimulated cells (Ellis et al, 1990;Settleman et al, 1992) and was then identified as a substrate of the Src kinase (Roof et al, 1998). In contrast to p190A, p190B is not abundantly phosphorylated in Src-transformed Rat-1 fibroblasts (Matheson et al, 2006). So far, no difference between the two isoforms has been found at the molecular level.…”

Section: Introductionmentioning

confidence: 88%

“…Both isoforms are involved in the same cellular pathways and both interact with p120 RasGAP, Rnd3 and TFII-I (GTF2I) (Burbelo et al, 1995;Jiang et al, 2005;Wennerberg et al, 2003). However, recent studies suggested that p190 RhoGAPs might play more-complex roles than previously thought, and are not solely limited to the regulation of RhoA activity (Matheson et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…In mouse embryos, both isoforms are highly expressed in the brain, in which they play both overlapping as well as specific roles. Mice lacking functional p190A exhibit several neuronal defects, reflecting a role for p190A in axon guidance and fasciculation (Brouns et al, 2001), whereas mice lacking p190B display axonal-tract deficits and neuronaldifferentiation defects, pointing to a role for p190B in normal brain development (Matheson et al, 2006). In addition, p190B-deficient mice are 30% reduced in size because of a defect in insulin and IGF1 signalling impacting on adipogenesis functions (Sordella et al, 2002;Sordella et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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p190B RhoGAP regulates endothelial-cell-associated proteolysis through MT1-MMP and MMP2

Guegan

Tatin

Lesté-Lasserre

et al. 2008

Journal of Cell Science

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The two isoforms of p190 RhoGAP (p190A and p190B) are important regulators of RhoGTPase activity in mammalian cells. Both proteins are ubiquitously expressed, are involved in the same signalling pathways and interact with the same identified binding partners. In search of isoform functional specificity, we knocked down the expression of each p190 protein using siRNA and examined the resulting phenotypic changes in human umbilical vein endothelial cells (HUVECs). We provide evidence that p190B plays a crucial role in the regulation of MT1-MMP expression and cell-surface presentation, as well as subsequent MMP2 activation. p190B is involved in both local extracellular matrix degradation at podosomes and endothelial cell assembly into tube-like structures in Matrigel. In addition, whereas p190B knockdown does not affect podosome formation, p190A knockdown increases the number of cells showing podosome structures in HUVECs. We conclude that the two p190 RhoGAP isoforms play distinct roles in endothelial cells. In addition, our data reveal an unsuspected role for p190B in the expression of the two collaborative proteases MT1-MMP and MMP2, thereby affecting matrix remodelling and angiogenesis.

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“…25 Finally, the presence of several functional domains suggests that GAPs may mediate signaling pathways that are not limited to Rho GTPase activity. 26 Therefore, defining the role of GAPs in vivo will probably help the identification of specific regulatory pathways that are critical for mammalian cell functions.p190-B RhoGAP (hereafter p190-B) serves as negative regulator of Rho activity. 27 Disruption of p190-B in gene-targeted mice has revealed defects in the central nervous system, thymus, and lung, which lead to perinatal lethality.…”

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confidence: 99%

Loss of the Rho GTPase activating protein p190-B enhances hematopoietic stem cell engraftment potential

Eleswarapu

Geiger

et al. 2009

Blood

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IntroductionHematopoietic stem cells (HSCs) are defined by their unique ability to give rise to all mature immune and blood cell lineages while at the same time regenerating themselves in a process termed "self-renewal" to sustain hematopoiesis throughout life. In addition, HSCs traffic throughout the body and possess the ability to reconstitute all hematopoietic lineages on transplantation into lethally irradiated mice, characteristics that have been used in therapeutic stem cell transplantation. [1][2][3] To maintain an adequate number of both mature blood cells and HSCs, the quality and quantity of HSC divisions must be tightly controlled. 4,5 Several regulatory pathways that play a role in the maintenance of HSC functions have been identified; these include both cell-intrinsic and extrinsic factors. For example, signaling through integrins, stem cell factor, thrombopoietin, angiopoietin, and transforming growth factor-␤ regulate HSC properties. [6][7][8][9] Cell-cycle regulators, p21 Cip1 , p16 Ink4a , p18 Ink4c , and p57 Kip2 , and proteins that control transcription, such as HoxB4, c-myc, FOXO, Zfx, Tel, Gfi-1, Pbx-1, or epigenetic factor, Bmi-1, and Ezh2, 4,5,[10][11][12][13][14][15] are essential for HSC functions. A fundamental issue in HSC biology is to understand how these programs are regulated and to exploit this knowledge for the development of HSC-based therapies for therapeutic purposes.Members of the Rho GTPase family operate as molecular switches to effect signaling downstream of numerous receptors, including integrins, chemokines and cytokine receptors. 16,17 Most canonical Rho GTPases cycle between an active guanosine triphosphate (GTP)-bound and an inactive guanosine diphosphate (GDP)-bound state. This GDP-GTP cycle is tightly regulated by 3 families of proteins. Guanine nucleotide exchange factors promote the exchange of GDP for GTP, whereas GTPase-activating proteins (GAPs) accelerate the rate of hydrolysis of GTP. In addition, guanine nucleotide dissociation inhibitors may interfere with GTP binding by preventing membrane localization of the protein. Of the 20 Rho GTPases currently known, the best studied Rho GTPases are Rho, Rac, and Cdc42, which are crucial regulators of cytoskeleton dynamics, cell migration, adhesion, and cell-cycle progression. As such, Rho GTPases regulate a broad variety of cellular processes in many mammalian cells, including in hematopoietic cells. [16][17][18][19][20][21][22][23] Whereas the role of Rho GTPases in cell functions has begun to be understood, the role of GAPs and guanine nucleotide exchange factors in vivo has been understudied. Because more than 70 RhoGAPs have been identified in eukaryotes, the RhoGAPs outnumber the Rho GTPases that they regulate. 24 Some GAPs show preferential tissue expression and appear to have tissuespecific functions. Moreover, each GAP can regulate a restricted number of Rho GTPase signaling pathways. 25 Finally, the presence of several functional domains suggests that GAPs may mediate signaling pathways that are not limite...

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Distinct but Overlapping Functions for the Closely Related p190 RhoGAPs in Neural Development

Cited by 27 publications

References 66 publications

VEGF-A stimulates podosome-mediated collagen-IV proteolysis in microvascular endothelial cells

VEGF-A stimulates podosome-mediated collagen-IV proteolysis in microvascular endothelial cells

p190B RhoGAP regulates endothelial-cell-associated proteolysis through MT1-MMP and MMP2

Loss of the Rho GTPase activating protein p190-B enhances hematopoietic stem cell engraftment potential

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