Trends in Cell Biology
Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis?
Section snippets
Ras interaction with multiple downstream effectors
Ras proteins are small GTP-binding and hydrolyzing proteins (GTPases) that exist in two distinct structural and functional confirmations: GTP-bound and active or GDP-bound and inactive 5, 7 (Figure 1). Ras proteins transition between the two nucleotide-bound states by: (i) hydrolyzing bound GTP to bound GDP; and (ii) nucleotide dissociation, facilitating exchange of bound GDP for free GTP in vivo. Intrinsic rates of GTP hydrolysis and nucleotide exchange by Ras proteins are too slow to
Raf and the ERK--MAPK cascade
The Raf serine/threonine kinases are the best-characterized and validated effectors of Ras function 6, 15. Although the three Raf isoforms share significant sequence similarities, they also exhibit distinct roles in development, in addition to significant biochemical and functional differences. In particular, the high basal kinase activity of B-Raf seems to be the basis for why only mutated forms of this isoform have been found in human cancers. Nevertheless, the isoforms show redundant
PI3K activation in human cancers
PI3K is the second best-characterized Ras effector, and has an important role in mediating the pro-survival and proliferative functions of Ras 4, 31 (Table 1 and Figure 2). The loss of the PTEN tumor suppressor supports the important contribution of PI3K hyperactivation in cancer development. Additionally, mutation of the PI3KCA gene encoding the p110α catalytic subunit of PI3K has been found in colorectal and other cancers [32]. The clustering and location of these missense mutations suggest
RalGEFs
RalGEFs were identified repeatedly in yeast two-hybrid screens for Ras-binding proteins and they link Ras proteins to activation of the RalA and RalB small GTPases 3, 35 (Table 1 and Figure 4). Four distinct RalGEFs have been identified as Ras effectors: RalGDS, RGL, RGL2 (also called Rlf ) and RGL3 (Figure 3c). To date, no reports of RalGEF or Ral mutations in human tumors have been described, but this is most likely because no efforts have been made to search for such mutations.
Initial studies
Tiam1 links Ras with Rho GTPases
There is considerable evidence that links the function of Rho-family GTPases, including Rac1 and RhoA, to Ras-mediated transformation [50]. Because aberrant Rho GTPase activation has been associated with promotion of tumor cell invasion and metastasis [51], it is logical to assume that effectors that facilitate Ras-mediated activation of Rho GTPases will be important in facilitating the role of oncogenic Ras in malignant tumor progression. One effector that provides this link is Tiam1, a Rac
RASSF-family proteins as Ras effectors and tumor suppressors
Recent studies have indicated that Ras effectors include protein products not only of oncogenes, but also of putative tumor suppressor genes. Such effectors might account for the growth-inhibitory and apoptotic activity of Ras seen in some situations 2, 4. The RASSF(1–6) gene family encodes RA-domain-containing proteins with no known catalytic function [2] (Table 1 and Figure 3c). Of these, a role as a Ras effector has been suggested for NORE1 (also called RASSF5), RASSF1, RASSF2 [55] and
Concluding remarks
Raf is perhaps the most important effector by which mutationally activated Ras promotes oncogenesis in mouse fibroblasts. However, experimental observations showing that activated Raf does not simply phenocopy Ras activation, together with findings of mutational activation or loss of expression of other effectors in cancers, clearly support the premise that Raf does not function alone in oncogenic transformation. An important issue in the dissection of effector function is the existence of
Acknowledgements
We thank Adrienne Cox and Chris Counter for critical comments, and Misha Rand for assistance in the preparation of illustrations. We apologize for not being able to cite the original work of many colleagues owing to space constraints. Our studies are supported by grants from the National Institutes of Health (CA42978, CA63071, CA69577 and GM65533). G.A.R. was supported as a Merck Fellow of the Life Sciences Research Foundation.
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