What tangled webs they weave: Rho-GTPase control of angiogenesis

Bryan, Brad Allen; D’Amore, P. A.

doi:10.1007/s00018-007-7008-z

Cited by 149 publications

(140 citation statements)

References 112 publications

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“…In this regard, it has been reported that the RhoA, Rac1, and Cdc42 small GTPases, key regulators of actin cytoskeleton dynamics, play a major role in vascular processes such as endothelial cell motility, angiogenesis, and endothelial cell permeability (30). When we investigated the activation of these GTPases by ANGPTL4, we found an induction of RhoA and Cdc42 activity in treated endothelial cells (Fig.…”

Section: Vegf Is Not Sufficient For the Exudative Phenotype In Vgpcr mentioning

confidence: 62%

Viral G protein-coupled receptor up-regulates Angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi's sarcoma

Jham

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

109

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Kaposi's sarcoma (KS) is an enigmatic vascular tumor thought to be a consequence of dysregulated expression of the human herpesvirus-8 (HHV-8 or KSHV)-encoded G protein-coupled receptor (vGPCR). Indeed, transgenic animals expressing vGPCR manifest vascular tumors histologically identical to human KS, with expression of the viral receptor limited to a few cells, suggestive of a paracrine mechanism for vGPCR tumorigenesis. Both human and vGPCR experimental KS lesions are characterized by prominent angiogenesis and vascular permeability attributed to the release of angiogenic molecules, most notably vascular endothelial growth factor. However, the relative contribution of these paracrine mediators to the angiogenic and exudative phenotype of KS lesions remains unclear. Here we show that vGPCR up-regulation of Angiopoietin-like 4 (ANGPTL4) plays a prominent role in promoting the angiogenesis and vessel permeability observed in KS. Indeed, ANGPTL4 expression is a hallmark of vGPCR experimental and human KS lesions. Inhibition of ANGPTL4 effectively blocks vGPCR promotion of the angiogenic switch and vascular leakage in vitro and tumorigenesis in vivo. These observations suggest that ANGPTL4 is a previously unrecognized target for the treatment of patients with KS. As angiogenesis and increased vessel permeability are common themes in all solid tumors, these findings may have a broad impact on our understanding and treatment of cancer.

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Section: Vegf Is Not Sufficient For the Exudative Phenotype In Vgpcr mentioning

confidence: 62%

Viral G protein-coupled receptor up-regulates Angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi's sarcoma

Jham

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

109

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“…These molecules may recruit Par-3 to the SC-axon interface, resulting in asymmetric localization and cytoskeletal reorganization by regulating actin and microtubule dynamics. Par-3 can regulate the Rho-family GTPases through GEFs (guanine nucleotide exchange factors) to mediate actin reorganization and possibly control axonal sorting and the unidirectional ensheathment of the axon (Benninger et al, 2007;Bryan and D'Amore, 2007;Nodari et al, 2007). Additionally, during asymmetric cell division, Par-3 recruits proteins such as Inscuteable, which in turn recruits Partner of Inscuteable (Pins) (Cai et al, 2003;Siller et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Assessing the Role of the Cadherin/Catenin Complex at the Schwann Cell–Axon Interface and in the Initiation of Myelination

Lewallen¹,

Shen²,

Torre³

et al. 2011

J. Neurosci.

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Myelination is dependent on complex reciprocal interactions between the Schwann cell (SC) and axon. Recent evidence suggests that the SC-axon interface represents a membrane specialization essential for myelination; however, the manner in which this polarized-apical domain is generated remains a mystery. The cell adhesion molecule N-cadherin is enriched at the SC-axon interface and colocalizes with the polarity protein Par-3. The asymmetric localization is induced on SC-SC and SC-axon contact. Knockdown of N-cadherin in SCs cocultured with DRG neurons disrupts Par-3 localization and delays the initiation of myelination. However, knockdown or overexpression of neuronal N-cadherin does not influence the distribution of Par-3 or myelination, suggesting that homotypic interactions between SC and axonal N-cadherin are not essential for the events surrounding myelination. To further investigate the role of N-cadherin, mice displaying SC-specific gene ablation of N-cadherin were generated and characterized. Surprisingly, myelination is only slightly delayed, and mice are viable without any detectable myelination defects. ␤-Catenin, a downstream effector of N-cadherin, colocalizes and coimmunoprecipitates with N-cadherin on the initiation of myelination. To determine whether ␤-catenin mediates compensation on N-cadherin deletion, SC-specific gene ablation of ␤-catenin was generated and characterized. Consistent with our hypothesis, myelination is more severely delayed than when manipulating N-cadherin alone, but without any defect to the myelin sheath. Together, our results suggest that N-cadherin interacts with ␤-catenin in establishing SC polarity and the timely initiation of myelination, but they are nonessential components for the formation and maturation of the myelin sheath.

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“…Candidates for such regulatory roles include members of the Rho-GTPase family of molecules, such as Rho and Rac1, which translate external signals into alterations in cytoskeletal reorganization and hence have the ability to influence migration. A large body of literature has characterized the cellular mechanisms and signal transduction pathways of Rho, Rho-dependent kinase (ROCK) and related regulatory members, such as Rac and PI3K, on cellular motility and chemotaxis in various cell types [29][30][31][32][33][34][35][36].…”

Section: Introductionmentioning

confidence: 99%

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

et al. 2011

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Adult neural precursor cells (NPCs) in the subventricular zone (SVZ) normally migrate via the rostral migratory stream (RMS) to the olfactory bulb (OB). Following neural injury, they also migrate to the site of damage. This study investigated the role of Rho-dependent kinase (ROCK) on the migration of NPCs in vitro and in vivo. In vitro, using neurospheres or SVZ explants, inhibition of ROCK using Y27632 promoted cell body elongation, process protrusion, and migration, while inhibiting NPC chain formation. It had no effect on proliferation, apoptosis, or differentiation. Both isoforms of ROCK were involved. Using siRNA, knockdown of both ROCK1 and ROCK2 was required to promote NPC migration and morphological changes; knockdown of ROCK2 alone was partially effective, with little/no effect of knockdown of ROCK1 alone. In vivo, infusion of Y27632 plus Bromodeoxyuridine (BrdU) into the lateral ventricle for 1 week reduced the number of BrdU-labeled NPCs in the OB compared with BrdU infusion alone. However, ROCK inhibition did not affect the tangential-to-radial switch of NPC migration, as labeled cells were present in all OB layers. The decrease in NPC number at the OB was not attributed to a decrease in NPCs at the SVZ. However, ROCK inhibition decreased the density of BrdU-labeled cells in the RMS and increased the distribution of these cells to ectopic brain regions, such as the accessory olfactory nucleus, where the majority differentiated into neurons. These findings suggest that ROCK signaling regulates NPC migration via regulation of cell-cell contact and chain migration.

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What tangled webs they weave: Rho-GTPase control of angiogenesis

Cited by 149 publications

References 112 publications

Viral G protein-coupled receptor up-regulates Angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi's sarcoma

Viral G protein-coupled receptor up-regulates Angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi's sarcoma

Assessing the Role of the Cadherin/Catenin Complex at the Schwann Cell–Axon Interface and in the Initiation of Myelination

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

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