Bustelo X R, Suen K L, Leftheris K, Meyers C A, Barbacid M
Department of Molecular Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543.
Oncogene. 1994 Aug;9(8):2405-13.
Vav is a proto-oncogene specifically expressed in cells of hematopoietic origin. Its gene product contains a series of structural motifs, including SH2 and SH3 domains, suggestive of a role in signal transduction. The Vav protein also possesses a Dbl-homology (DH) domain previously found in regulators of the Ras superfamily of small GTP-binding proteins. Recently, Vav has been reported to be the major Ras GDP/GTP exchange factor (GEF) in hematopoietic cells [Gulbins et al., Science 260, 822 (1993); J. Immunol. 152, 2123 (1994)]. The following observations are inconsistent with such a role: (i) Vav proteins do not exhibit Ras GEF activity in standard GDP/GTP exchange assays; (ii) Cells overexpressing Vav do not have increased levels of GTP-bound Ras proteins; (iii) Overexpression of Vav does not overcome the growth inhibitory activity of RasN17, a mutant that blocks Ras signaling by inhibiting Ras GEFs; (iv) Transformation of NIH3T3 cells by Vav oncoproteins is not inhibited by a farnesyl transferase inhibitor that completely blocks transformation by both Ras and its well characterized GEF, RasCDC25 and (v) The morphology of Vav-transformed NIH3T3 cells is dramatically different from that induced by Ras and RasCDC25. Whereas these observations make it unlikely that Vav functions either as a RasGEF or as an upstream regulatory element of Ras, we have observed that Vav can cooperate with normal Ras proteins to transform NIH3T3 cells. These results suggest that Vav and Ras may mediate signal transduction by distinct, but interactive mitogenic pathways.
Vav是一种原癌基因，在造血起源的细胞中特异性表达。其基因产物包含一系列结构基序，包括SH2和SH3结构域，提示其在信号转导中发挥作用。Vav蛋白还具有一个先前在小GTP结合蛋白Ras超家族的调节因子中发现的Dbl同源（DH）结构域。最近，有报道称Vav是造血细胞中的主要Ras GDP/GTP交换因子（GEF）[古尔宾斯等人，《科学》260, 822（1993）；《免疫学杂志》152, 2123（1994）]。以下观察结果与这种作用不一致：（i）在标准的GDP/GTP交换试验中，Vav蛋白不表现出Ras GEF活性；（ii）过表达Vav的细胞中GTP结合的Ras蛋白水平没有增加；（iii）Vav的过表达不能克服RasN17的生长抑制活性，RasN17是一种通过抑制Ras GEF来阻断Ras信号传导的突变体；（iv）法尼基转移酶抑制剂不能抑制Vav癌蛋白对NIH3T3细胞的转化，而该抑制剂能完全阻断Ras及其特征明确的GEF RasCDC25的转化；（v）Vav转化的NIH3T3细胞的形态与Ras和RasCDC25诱导的形态有显著差异。尽管这些观察结果表明Vav不太可能作为RasGEF或Ras的上游调节元件发挥作用，但我们观察到Vav可以与正常的Ras蛋白协同作用来转化NIH3T3细胞。这些结果表明，Vav和Ras可能通过不同但相互作用的促有丝分裂途径介导信号转导。
