Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis?

doi:10.1016/j.tcb.2004.09.014

Trends in Cell Biology

Volume 14, Issue 11, November 2004, Pages 639-647

https://doi.org/10.1016/j.tcb.2004.09.014 Get rights and content

Ras proteins function as signal transducers and are mutationally activated in many human cancers. In 1993, Raf was identified as a key downstream effector of Ras signaling, and it was believed then that the primary function of Ras was simply to facilitate Raf activation. However, the subsequent discovery of other proteins that are effectors of Ras function suggested that oncogenic activities of Ras are mediated by both Raf-dependent and Raf-independent signaling. Further complexity arose with the identification of Ras effectors with putative tumor suppressor, rather than oncogenic, functions. However, the recent identification of B-raf mutations in human cancers has renewed the debate regarding whether Raf activation alone promotes Ras-mediated oncogenesis. In this article, we summarize the current knowledge of the contribution of Ras effectors in Ras-mediated 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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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

Raf and the ERK--MAPK cascade

PI3K activation in human cancers

RalGEFs

Tiam1 links Ras with Rho GTPases

RASSF-family proteins as Ras effectors and tumor suppressors

Concluding remarks

Acknowledgements

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