Vav1 is physiologically active as a GDP/GTP nucleotide exchange factor (GEF) in the hematopoietic system. Overexpression of Vav1 in multiple tumor types is known to enhance oncogenicity, yet whether or not Vav1 is a bona fide oncogene is still a matter of debate. Although mutations in Vav1 were recently identified in human cancers of various origins, the functional activities of these mutants are not known. We tested the transforming potential of three mutations identified in human lung adenocarcinoma: E59K, D517E, and L801P. Results from several assays indicative of transforming activities such as rate of proliferation, growth in agar, and generation of tumors in NOD/SCID mice clearly indicated that E59K and D517E are highly transforming but L801P at the SH3 domain is not. The acquired oncogenic activity of these mutants can be attributed to their enhanced activity as GEFs for Rho/Rac GTPases. Deciphering of the mechanisms leading to overactivity of the tested mutants revealed that the E59K mutation facilitates cleavage of a truncated protein that is uncontrollably active as a GEF, while D517E generates a highly stable overexpressed protein that is also more active as a GEF than wild-type Vav1. These findings support the classification of Vav1 as a bona fide oncogene in human cancer.
Bibliographical noteFunding Information:
We are thankful to Shirley Smith for editing the manuscript, to Professor Ora Schueler-Furman for advice on the Vav1 mutants and to Dr. Volker Stucke for providing the initial mutant plasmids. This work was partially supported by grants from the Israel Academy of Sciences; Israel Cancer Research Foundation; the Israeli Cancer Association (ICA), with the generous assistance of the London friends of ICA in memory of the late Haim Yacobi; The Hubert H. Humphrey Center for Experimental Medicine and Cancer Research; The Alex U. Soyka Pancreatic Cancer Research Program; and a donation from Vibeke Lichten.
© 2018, The Author(s).