Multifaceted role of Rho proteins in angiogenesis
ABSTRACT The Rho family of GTPases is part of the Ras superfamily. The Rho, Rac, and Cdc42 members of the family are present in mammalian cells and have been the subject of attention of researchers due to their vast spectrum of functions. Rac 1, Cdc42, and RhoA are well-known for their role in the regulation of the actin cytoskeleton in promoting the formation of lamellipodia, filopodia, and stress fibers, respectively. The Rho proteins also participate in the control of cell growth, motility, cell-cell adhesions, morphogenesis, cytoskeletal dynamics, and cellular trafficking. The mechanisms for eliciting these functions have become clearer during the last decade. Concordant with their roles in multiple processes of cellular control, the Rho proteins have been shown to be involved in tumor growth, progression, metastasis, and now angiogenesis.
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- "Many Ras family members and their regulators have been implicated in vascular development (Gitler et al., 2003; Henkemeyer et al., 1995; Tan et al., 2008), including EC migration (Sosnowski et al., 1993; Tan et al., 2008), capillary tube assembly (Connolly et al., 2002), angiogenesis (Aitsebaomo et al., 2004; Fryer and Field, 2005; Kranenburg et al., 2004; Merajver and Usmani, 2005), blood vessel homeostasis (Komatsu and Ruoslahti, 2005) and vascular permeability (Serban et al., 2008). Ras molecules are small GTPases widely shown to function as molecular switches coordinating multiple cellular behaviors like growth, proliferation, migration and differentiation. "
ABSTRACT: Ras proteins are small GTPases that regulate cellular growth and differentiation. Components of the Ras signaling pathway have been shown to be important during embryonic vasculogenesis and angiogenesis. Here, we report that Rasip1, which encodes a novel Ras-interacting protein, is strongly expressed in vascular endothelial cells throughout development, in both mouse and frog. Similar to the well-characterized vascular markers VEGFR2 and PECAM, Rasip1 is specifically expressed in angioblasts prior to vessel formation, in the initial embryonic vascular plexus, in the growing blood vessels during angiogenesis and in the endothelium of mature blood vessels into the postnatal period. Rasip1 expression is undetectable in VEGFR2 null embryos, which lack endothelial cells, suggesting that Rasip1 is endothelial specific. siRNA-mediated reduction of Rasip1 severely impairs angiogenesis and motility in endothelial cell cultures, and morpholino knockdown experiments in frog embryos demonstrate that Rasip1 is required for embryonic vessel formation in vivo. Together, these data identify Rasip1 as a novel endothelial factor that plays an essential role in vascular development.Developmental Biology 04/2009; 329(2):269-79. DOI:10.1016/j.ydbio.2009.02.033 · 3.64 Impact Factor
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- "Expression of MMP genes is transcriptionally regulated by a variety of extracellular factors, including cytokines and growth factors, as well as signals from the ECM. Because RhoA regulates several steps of the angiogenic programme (Merajver and Usmani, 2005), we examined the role played by p190 isoforms in endothelial cells. Here, we provide data showing that the two p190 isoforms play distinct roles associated with endothelial cell invasiveness. "
ABSTRACT: 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.Journal of Cell Science 07/2008; 121(Pt 12):2054-61. DOI:10.1242/jcs.025817 · 5.33 Impact Factor
- "Some reports indicate that RhoA, RhoC and their downstream target ROCK are needed for cancer cell extravasation, but these studies are largely based on chemical inhibitors that are not completely specific . Interestingly, RhoC can induce the production of angiogenic factors in breast cancer, and this could help promote entry into blood vessels and thereby metastasis . More extensive work is needed to elucidate the possible contribution of Rho GTPases to the extravasation of cancer cells. "
Article: Rho GTPases in cancer cell biology[Show abstract] [Hide abstract]
ABSTRACT: Rho GTPases contribute to multiple cellular processes that could affect cancer progression, including cytoskeletal dynamics, cell cycle progression, transcriptional regulation, cell survival and vesicle trafficking. In vitro several Rho GTPases have oncogenic activity and/or can promote cancer cell invasion, and this correlates with increased expression and activity in a variety of cancers. Conversely, other family members appear to act as tumour suppressors and are deleted, mutated or downregulated in some cancers. Genetic models are starting to provide new information on how Rho GTPases affect cancer development and progression. Here, we discuss how Rho GTPases could contribute to different steps of cancer progression, including proliferation, survival, invasion and metastasis.FEBS Letters 07/2008; 582(14):2093-101. DOI:10.1016/j.febslet.2008.04.039 · 3.34 Impact Factor