Expression cloning of lsc, a novel oncogene with structural similarities to the Dbl family of guanine nucleotide exchange factors

Abstract

In a screen for genes with oncogenic potential expressed by the murine B6SUtA1 myeloid progenitor cell line, we isolated a 2.5-kilobase pair cDNA whose expression causes strong morphological transformation and deregulated proliferation of NIH 3T3 cells. The transforming cDNA encodes a truncated protein (designated Lsc) with a region of sequence similarity to the product of the lbc oncogene. This region includes the tandem Dbl homology and pleckstrin homology domains that are hallmarks of the Dbl-like proteins, a family of presumptive or demonstrated guanine nucleotide exchange factors that act on Rho family GTPases. Lsc requires intact Dbl homology and pleckstrin homology domains for its oncogenic activity. The transforming activity of Lsc in NIH 3T3 cells is reduced by cotransfection with p190 (a GTPase activating protein for Rho family GTPases) and the Rho family dominant-negative mutants RhoA(19N), CDC42(17N), and Rac1(17N). These results indicate a role for the Rho family of GTPases in mediating the transforming activity of Lsc and are consistent with the exchange specificities that have been attributed to Dbl family members. The lsc gene is expressed in a variety of tissues and is particularly abundant in hemopoietic tissues (thymus, spleen, and bone marrow). Lsc is a member of a growing family of proteins that may function as activators of Rho family GTPases in a developmental or tissue-specific manner.