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Review
. 1995;4(6):345-56.

Signal transduction by Ras-like GTPases: a potential target for anticancer drugs

M Spaargaren  1 , J R Bischoff, F McCormick
Affiliations
Review

Signal transduction by Ras-like GTPases: a potential target for anticancer drugs

M Spaargaren et al. Gene Expr. 1995.

Abstract

Members of the ras family of GTPases are involved in a wide variety of cellular processes including cell proliferation, differentiation, apoptosis, and transformation. The ras oncogene is one of the most frequently mutated genes in human cancer. In addition, other oncogene and tumor suppressor gene products are components of the signal transduction pathways in which Ras or other Ras-like GTPases play key regulatory functions. Current progress in the elucidation of these signal transduction pathways will be reviewed and the potential use of these insights for the development of novel therapeutic agents for the treatment of cancer will be discussed.

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Figures

FIG. 1
FIG. 1
Signal transaction by Ras-like GTPases. Ras-like GTPases (Ras) are posttranslationally modified by prenyltransferases (PTs), resulting in their membrane localization. Their activity is regulated by GTPases activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs), resulting in their inactive GDP- or active GTP-bound state, respectively. In their biologically active GTP-bound state the Ras-like GTPases couple to effector molecules, which transmit the signal further downstream in the signal transduction pathway.
FIG. 2
FIG. 2
Growth factor-induced Ras activation. The mechanism by which EGF activates Ras. Upon binding of EGF to the EGF receptor, the receptors dimerize as a consequence of which the intrinsic tyrosine kinase of the receptor becomes activated, resulting in autophosphorylation of the receptor by intermolecular cross-phosphorylation. The phosphorylated tyrosine residues of the EGF receptor provide a binding site for the SH2 domain of Grb2. Grb2 is complexed with the RasGEF Sos by its SH3 domains that bind a proline-rich sequence in Sos. Probably as a consequence of the recruitment of Grb2 by the autophosphorylated receptor tyrosine kinase, Sos is translocated to the plasma membrane in the proximity of Ras, thereby resulting in Ras activation.
FIG. 3
FIG. 3
Ras-mediated activation of Raf and signaling downstream of Raf. Activated Ras recruits Raf to the plasma membrane by a direct interaction. At the plasma membrane Raf is activated, a process that may involve the protein 14-3-3 and/or another unknown factor (X). As a consequence of the activation of Raf, Raf phosphorylates and activates MEK (and other substrates?), which in its turn phosphorylates and activates MAP kinase (and other substrates?). The MAP kinase can phosphorylate a number of substrates, including other kinases as well as several transcription factors, thereby regulating the transcriptional control of their target genes.
FIG. 4
FIG. 4
Cross-talk between different Ras-like GTPases. Different stimuli (X, Y, and Z) may result in the activation of different, or a particular combination of, Ras-like GTPases (R-ras, Ras, and Rap). The final biological outcome of these stimuli will be determined by which of the effector molecules (Raf and RalGDS) of these GTPases are subsequently activated or inactivated. For example, activation of Ras stimulates (closed arrow) Raf, whereas activation of Rap inhibits (blunt arrow) activation of Raf. The effect of the activation of R-ras on Raf activity is unknown (open arrow). Whereas activation of the Raf pathway is involved in mitogenesis, the biological effect of the interaction of the Ras-like GTPases with RalGDS, as well as the effect of the interaction between Bcl-2 (which suppresses apoptosis) and R-ras, remains to be established. AFs are apoptosis-inducing factors, SFs are survival factors, and GFs are growth factors.
FIG. 5
FIG. 5
Potential target sites in the signal transduction pathways of Ras-like GTPases for the development of anticancer drugs. Schematic representation of anticancer drug targets in the Ras-like GTPase signaling pathways, focusing on drugs that counteract the effect of oncogenic mutants of Ras and upstream tyrosine kinases. For an explanation of the potential anticancer drug targets and the underlying biological principle, see the text. A stimulatory effect is indicated by the closed arrow, a suppressing effect by a blunted arrow, and an unknown effect by the open arrow. FT is farnesyltransferases, PKA is protein kinase A.
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