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Abstract
Many deregulated signal transducer proteins are involved in various cancers at numerous stages of tumor development. One of these, Vav1, is normally expressed exclusively in the hematopoietic system, where it functions as a specific GDP/GTP nucleotide exchange factor (GEF), strictly regulated by tyrosine phosphorylation. Vav was first identified in an NIH3T3 screen for oncogenes. Although the oncogenic form of Vav1 identified in the screen has not been detected in clinical human tumors, its wild-type form has recently been implicated in mammalian malignancies, including neuroblastoma, melanoma, pancreatic, lung and breast cancers, and B-cell chronic lymphocytic leukemia. In addition, it was recently identified as a mutated gene in human cancers of various origins. However, the activity and contribution to cancer of these Vav1 mutants is still unclear. This review addresses the physiological function of wild-type Vav1 and its activity as an oncogene in human cancer. It also discusses the novel mutations identified in Vav1 in various cancers and their potential contribution to cancer development as oncogenes or tumor suppressor genes.
Highlights
The past few decades have witnessed a major leap in understanding of the molecular mechanisms involved in tumor pathogenesis and progression [1]
As shown in pancreatic cancer cells, EGF stimulation leads to tyrosine phosphorylation of Vav1, followed by the activation of a Rac1/Pak1/Nuclear Factor κB (NF-κB) signaling pathway resulting in an increase in cyclin D1 which leads to enhanced pancreatic tumor cell proliferation [69]
While Vav1 was first identified as an oncogene capable of inducing transformation in NIH3T3 fibroblasts, accumulating results from the past decade clearly indicate its participation in human cancer through ectopic overexpression
Summary
The past few decades have witnessed a major leap in understanding of the molecular mechanisms involved in tumor pathogenesis and progression [1]. As shown in pancreatic cancer cells, EGF stimulation leads to tyrosine phosphorylation of Vav, followed by the activation of a Rac1/Pak1/NF-κB signaling pathway resulting in an increase in cyclin D1 which leads to enhanced pancreatic tumor cell proliferation [69] This recurring theme suggests that Vav might contribute to the progression of cancer by regulating www.impactjournals.com/oncotarget secretion of autocrine ligands critical for tumorigenicity, as well as affecting the expression of other proteins critical for various cellular functions. Reduction of Vav and Vav expression in mouse mammary tumor cells led to a decline in metastatic growth, similar to the effect of Vav depletion in pancreatic cancer cells [114] These results further highlight the fact that the various members of the Vav family of proteins, Vav, Vav and Vav, may have different roles in human cancer
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