Vav2 Is an Activator of Cdc42, Rac1, and RhoA

Abe, Karon; Rossman, Kent L.; Liu, Betty; Ritola, Kimberly; Chiang, Derek Y.; Campbell, Sharon L.; Burridge, Keith; Der, Channing J.

doi:10.1074/jbc.275.14.10141

Cited by 244 publications

(252 citation statements)

References 48 publications

(84 reference statements)

Supporting

Mentioning

236

Contrasting

Unclassified

Order By: Relevance

“…16 Activation of Rho/Rac proteins also can lead to cellular transformation and oncogenesis, either by enhancing the metastatic properties of transformed cells or by serving as secondary factors that contribute to the transforming activities of oncoproteins such as Ras. 19,20 Stat5 has also been shown to contribute to the oncogenesis of human breast carcinoma by playing an important role in controlling cell-cycle progression and apoptosis. 21 Given these data, one hypothesis to be tested was that the expression of Vav2 would increase in malignant tissues as compared to benign tissues in response to its increased role of stimulating Rac1 and Stat5-mediated gene transcription in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Altered expression of prolactin receptor-associated signaling proteins in human breast carcinoma

et al. 2008

View full text Add to dashboard Cite

Prolactin receptor signaling can modulate proliferation, survival, motility, angiogenesis, and differentiation in breast cancer. Increased serum prolactin is associated with a significantly increased risk of breast cancer in post-menopausal women. The purpose of this study was to examine the expression of prolactin receptorassociated signaling proteins in breast cancer vs benign breast tissue. Breast tissue microarrays representing 40 cases of benign and malignant pathologies were obtained from the Cooperative Human Tissue Network. Standard immunohistochemistry for prolactin and prolactin receptor-associated proteins was performed. Both positive regulators (c-Myb, Nek3, Vav2) and negative regulators (PIAS3, SIRP) of prolactin receptor signaling were examined. Virtual slides were created from the stained breast tissue microarrays. Labels were scored by region of interest and labeling indices incorporating percent target labeled and label intensity were created. Quantitative determinations of labels were made using the Clarient image system. The unpaired t-test was used to compare labels from benign and malignant tissues. Visual scoring data showed upregulation of Nek3 (P ¼ 0.000377), PIAS3 (P ¼ 0.000257), and prolactin (P ¼ 0.002576) in breast cancer vs normal/hyperplastic epithelium. c-Myb showed a trend toward upregulation, but this did not achieve statistical significance (P ¼ 0.107374). SIRP (P ¼ 0.002060) was downregulated. Vav2 showed a trend toward downregulation (P ¼ 0.107456), but this did not achieve statistical significance. Clarient analysis corroborated upregulation in cancer of Nek3 (P ¼ 0.000013), PIAS3 (P ¼ 0.000067), and prolactin (P ¼ 0.017569). In conclusion, regulators of prolactin receptor signaling show heterogeneity in their expression in benign vs malignant breast tissue. Since these species are known to regulate prolactin-mediated actions, these results suggest multiple targets for modulating prolactin receptor-mediated growth and differentiation in breast cancer. The neuroendocrine hormone prolactin contributes to breast cancer progression through both endocrine and autocrine/paracrine loops. Prolactin acts through its cell-surface receptor, the prolactin receptor, and triggers a network of prolactin receptor-associated signaling proteins. In normal tissues, prolactin stimulates lobulo-alveolar expansion and differentiation as a prelude to milk synthesis and secretion. 1 In malignant tissues, however, prolactin fails to trigger differentiation, and instead enhances breast epithelial survival and motility. [2][3][4] Both normal and malignant breast epithelia, besides responding to pituitary-secreted (endocrine) prolactin, synthesize prolactin RNA from an upstream promoter at the autocrine/paracrine level. 4 As mutations of the prolactin receptor are very infrequent in breast cancer, we hypothesized that dysregulation of local prolactin production or prolactin receptor-associated signaling machinery may contribute to some of the altered actions of prolactin in this disease.This study focus...

show abstract

Section: Discussionmentioning

confidence: 99%

Altered expression of prolactin receptor-associated signaling proteins in human breast carcinoma

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Various lines of evidence have implicated Src as being downstream of the EGF receptor (30 -33), although the exact mechanism by which the treatment of cells with EGF results in the activation of the Src tyrosine kinase has not yet been determined. However once activated, Src can phosphorylate Vav2, thereby stimulating its GEF activity, a mechanism that has been well established (39,40,44). The activated Vav2 then directly catalyzes GDP-GTP exchange on Cdc42.…”

Section: Discussionmentioning

confidence: 99%

“…The originally identified Vav protein (Vav1) was shown to be hematopoietic-specific, whereas a second form, Vav2, was found to be much more widely distributed. It has been well established that the Vav proteins are activated following their phosphorylation by Src and related tyrosine kinases (24 -26) and that Vav2 exhibits GEF activity toward Cdc42 as well as Rac (39,40). Fig.…”

Section: Fig 6 Egf-dependent Activation Of Cdc42 Is Inhibited By a mentioning

confidence: 99%

Epidermal Growth Factor-dependent Regulation of Cdc42 Is Mediated by the Src Tyrosine Kinase

Wang

et al. 2003

Journal of Biological Chemistry

102

View full text Add to dashboard Cite

Cdc42 is a member of the Rho subfamily of Ras-related GTP-binding proteins and has been implicated in a wide range of cellular processes and signaling activities. Among its best known actions is the regulation of actin cytoskeletal architecture, because microinjection of activated Cdc42 was found to give rise to filopodia formation, whereas the closely related Rac and RhoA proteins were implicated in membrane ruffling and in the generation of actin stress fibers, respectively (1-4). A number of lines of evidence have also implicated Cdc42 in the control of normal cell growth and, when hyperactivated, in cellular transformation. These include the findings that Dbl (for diffuse B cell lymphoma) and a number of related guanine nucleotide exchange factors (GEFs) 1 for Cdc42 and other Rho proteins are capable of transforming cells and that mutations in Cdc42 that mimic the actions of GEFs and allow the spontaneous exchange of GDP for GTP exhibit oncogenic activity (5-10).

show abstract

“…In contrast to RhoA, Rac and Cdc42 can be activated by PKA without direct phosphorylation [25,26], but via activation of guanine nucleotide exchange factors (GEFs)Tiam1 and Trio, which have consensus PKA phosphorylation sites [27]. Another GEF Vav2 demonstrates strong GEF exchange activity toward Rac1 and Cdc42 [28]. Phosphorylation of Vav2 by Src family tyrosine kinases at Y174 induces conformational change and makes Vav2 DH domain available for interaction with Rac [29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Prostaglandins PGE2 and PGI2 promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation

Birukova

Zagranichnaya

et al. 2007

Experimental Cell Research

265

267

View full text Add to dashboard Cite

Prostaglandin E 2 (PGE 2 ) and prostacyclin are lipid mediators produced by cyclooxygenase and implicated in the regulation of vascular function, wound repair, inflammatory processes, and acute lung injury. Although protective effects of these prostaglandins (PGs) are associated with stimulation of intracellular cAMP production, the crosstalk between cAMP-activated signal pathways in the regulation of endothelial cell (EC) permeability is not well understood. We studied involvement of cAMP-dependent kinase (PKA), cAMP-Epac-Rap1 pathway, and small GTPase Rac in the PGsinduced EC barrier protective effects and cytoskeletal remodeling. PGE 2 and PGI 2 synthetic analog beraprost increased transendothelial electrical resistance and decreased dextran permeability, enhanced peripheral F-actin rim and increased intercellular adherens junction areas reflecting EC barrier-protective response. Furthermore, beraprost dramatically attenuated thrombin-induced Rho activation, MLC phosphorylation and EC barrier dysfunction. In vivo, beraprost attenuated lung barrier dysfunction induced by high tidal volume mechanical ventilation. Both PGs caused cAMPmediated activation of PKA-, Epac/Rap1-and Tiam1/Vav2-dependent pathways of Rac1 activation and EC barrier regulation. Knockdown of Epac, Rap1, Rac-specific exchange factors Tiam1 and Vav2 using siRNA approach, or inhibition of PKA activity decreased Rac1 activation and PGinduced EC barrier enhancement. Thus, our results show that barrier-protective effects of PGE 2 and prostacyclin on pulmonary EC are mediated by PKA and Epac/Rap pathways, which converge on Rac activation and lead to enhancement of peripheral actin cytoskeleton and adherens junctions. These mechanisms may mediate protective effects of PGs against agonist-induced lung vascular barrier dysfunction in vitro and against mechanical stress-induced lung injury in vivo.

show abstract

Vav2 Is an Activator of Cdc42, Rac1, and RhoA

Cited by 244 publications

References 48 publications

Altered expression of prolactin receptor-associated signaling proteins in human breast carcinoma

Altered expression of prolactin receptor-associated signaling proteins in human breast carcinoma

Epidermal Growth Factor-dependent Regulation of Cdc42 Is Mediated by the Src Tyrosine Kinase

Prostaglandins PGE2 and PGI2 promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation

Contact Info

Product

Resources

About