Rac is required for v-Abl tyrosine kinase to activate mitogenesis

The v-abl oncogene of the Abelson murine leukemia virus (A-MuLV) encodes a cytoplasmic tyrosine kinase that can associate with phosphoinositide 3-kinase, Shc and Grb2, and activate the pathway that leads from Ras to mitogen-activated protein (MAP) kinase. Despite the link to these mitogenic signal transducers, v-Abl does not stimulate cell growth in general. Only a subset of NIH3T3 cells, represented by the P-3T3 subclone, can respond to the mitogenic effects of v-Abl, whereas the majority of NIH3T3 cells respond to the growth-inhibitory effects of v-Abl. This restricted mitogenic function suggests that v-Abl may rely on additional signal transducers--which are not required for the physiological mitogenic response--to stimulate DNA synthesis.

A dominant-negative mutant of the small GTP-binding protein Rac (Rac N17, containing an asparagine residue at position 17) was found to block v-Abl-induced activation of two mitogenic enhancer elements. Activation of the serum response element by v-Abl was inhibited by Rac N17 and Ras N17, whereas activation of the TPA response element was inhibited by Rac N17 but not by Ras N17. The Rac N17 mutant also compromized the ability of v-Abl to activate the MAP-kinase, Erk2, and the stress-activated protein kinase, JNK1. Activation of endogenous Rac was indicated by the ability of v-Abl to stimulate pinocytosis. P-3T3 cells transformed by v-abl could proliferate without serum, but became serum-dependent when Rac N17 was expressed. However, Rac N17 did not inhibit the morphological change or anchorage-independent growth of cells transformed with v-Abl.

The activation of the mitogenic program by v-Abl tyrosine kinase requires not only Ras but also Rac. Multiple pathways are activated by v-Abl in transformed cells. The availability of some of these pathways may determine whether v-Abl can activate mitogenesis.