ras Proto-Oncogene Activation in Human Malignancy

Abstract

The three members of the human ras family of proto-oncogenes (H-ras, K-ras, and N-ras) encode highly related, low-mol-wt (21 kDa), guanine nucleotide (GDP and GTP) binding proteins that are located at the inner face of the plasma membrane (Barbacid, 1987). The Ras proteins are believed to function as molecular switches that regulate the passage of mitogenic signals from growth factor receptors to the nucleus via signal transduction pathways involved in cell proliferation (Bourne et al., 1990a,b; Egan and Weinberg, 1993). The Ras proteins perform this activity by a regulated GDP/GTP cycle, much in the manner of the well-characterized heterotrimeric G proteins, that involves their shuttling between inactive, GDP-bound and active, GTP-bound states (Gilman, 1984). Thus, an appropriate mitogenic signal causes a transient increase in the level of GTP-bound Ras, which then associates with an as yet unidentified downstream effector target to mediate the passage of the signal before being rapidly returned to the inactive, GDP-bound form, thereby terminating the mitogenic response (Satoh et al., 1992). Oncogenic mutations cause a deregulation of the GDP/GTP cycle, lock the protein in the active, GTP-bound state, and consequently result in the constitutive activation of Ras-mediated stimulation of cellular proliferation.