Trends in Cell Biology
ReviewUnderstanding Ras: ‘it ain’t over ’til it’s over’
Section snippets
The multiple effectors of Ras: Raf is not enough
It is well appreciated that the activation of diverse cell-surface receptors can stimulate convergent signals that lead to the activation of Ras. Once activated, Ras was once believed to activate a simple linear cascade of cytoplasmic kinases to complete the link between the cell surface and the nucleus. However, recent studies have clearly established that activated Ras stimulates a multitude of downstream signalling cascades. Ras activation of the Raf serine/threonine kinases and the
Rho family proteins: mediators of growth, invasion and metastasis?
The inhibition of Ras transformation by dominant–negative mutants of specific Rho family proteins (RhoA, RhoB, RhoG, Rac1, Cdc42 and TC10), coupled with the ability of activated Rho family members to cooperate with Raf to cause synergistic transformation, has implicated these proteins as key mediators of Ras transformation5, 22. Microinjection studies, together with genetic studies, implicate Rho proteins as downstream components of Ras signalling. However, many questions regarding the
Cell-type differences in Ras signalling and transformation: is there no one right answer?
Much of our understanding of Ras function is derived from the study of Ras transformation of rodent fibroblast cell lines. There is no dispute regarding the immense value of rodent fibroblast cell systems to study Ras function. However, the fact that ras mutations occur most frequently in human cancers that arise from epithelial and haematopoietic cells31, 32 prompts the question of whether fibroblast-based studies have provided a meaningful, or misleading, notion of what Ras really does in
Multiple Ras proteins: why so many?
The existence of multiple Ras and Ras-related proteins adds yet another potential layer of complexity to understanding Ras function. The high degree of sequence identity (Fig. 3), coupled with the essentially identical ability of mutated forms of H-Ras, the two K-Ras isoforms (4A and 4B) and N-Ras to cause transformation of NIH 3T3 and other cell types, have lulled us into a mindset that all Ras proteins were created equal. Hence, in large part due simply to the wider availability of reagents
Complications of experimental analyses
Aside from the issues raised above, some additional concerns regarding how we study Ras signalling and biology need to be considered. First, a majority of experimental studies utilize ectopic overexpression of Ras and other Ras signalling components. Overexpressed proteins might exhibit functions not seen at physiological levels of expression. For example, activation of endogenous Ras is not always associated with activation of Raf, PI3K/Akt or other effector pathways. Quantitative differences
Concluding remarks
In summary, although our understanding of Ras as a signalling molecule in normal and neoplastic cells is quite impressive and considerable, much more remains to be revealed. We have highlighted five issues regarding the study of Ras that have emerged and that have complicated a straightforward delineation of Ras function. First, Ras utilizes a spectrum of functionally diverse proteins, and more effectors will certainly be found. Second, the interplay between Ras and Ras-related small GTPases is
Acknowledgements
We thank Adrienne Cox for critical comments of this manuscript and Misha Rand for excellent assistance in manuscript and figure preparation. Our sincere apologies to those whose original work, owing to space limitations, could not be discussed or cited. Our studies were supported by a Department of Defense fellowship to J.S., a National Science Foundation fellowship to K.P., a National Cancer Institute fellowship to A.M. and National Cancer Institute grants to C.J.D.
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