Trends in Cell Biology
Volume 10, Issue 4, 1 April 2000, Pages 147-154
Journal home page for Trends in Cell Biology

Review
Understanding Ras: ‘it ain’t over ’til it’s over’

https://doi.org/10.1016/S0962-8924(00)01740-2Get rights and content

Abstract

Since 1982, Ras has been the subject of intense research scrutiny, focused on determining the role of aberrant Ras function in human cancers and defining the mechanism by which Ras mediates its actions in normal and neoplastic cells. The long-term goal has been to develop antagonists of Ras as novel approaches for cancer treatment. Although impressive strides have been made in these endeavours, and our knowledge of Ras is quite extensive, it appears that we are at the beginning, rather than at the end, of fully understanding Ras function. This review highlights new issues that have further complicated our efforts to understand Ras.

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.

References (55)

  • M. Serrano

    Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a

    Cell

    (1997)
  • E. Choy

    Endomembrane trafficking of ras: the CAAX motif targets proteins to the ER and Golgi

    Cell

    (1999)
  • S.J. Taylor et al.

    Cell cycle-dependent activation of Ras

    Curr. Biol.

    (1996)
  • S.L. Campbell

    Increasing complexity of Ras signaling

    Oncogene

    (1998)
  • I.M. Zohn

    Rho family proteins and Ras transformation: the RHOad less traveled gets congested

    Oncogene

    (1998)
  • A. Khwaja

    Akt is more than just a Bad kinase

    Nature

    (1999)
  • K. Irani

    Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts

    Science

    (1997)
  • J.A. Romashkova et al.

    NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling

    Nature

    (1999)
  • O.N. Ozes

    NF-kappaB activation by tumour necrosis factor requires the Akt serine–threonine kinase

    Nature

    (1999)
  • M.W. Mayo

    Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras

    Science

    (1997)
  • S.M. Frisch

    Control of adhesion-dependent cell survival by focal adhesion kinase

    J. Cell Biol.

    (1996)
  • A. Khwaja

    Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway

    EMBO J.

    (1997)
  • J. Zhu

    Senescence of human fibroblasts induced by oncogenic Raf

    Genes Dev.

    (1998)
  • A.W. Lin

    Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling

    Genes Dev.

    (1998)
  • M.B. Ramocki

    Signaling through mitogen-activated protein kinase and Rac/Rho does not duplicate the effects of activated Ras on skeletal myogenesis

    Mol. Cell. Biol.

    (1997)
  • L. Van Aelst et al.

    Rho GTPases and signaling networks

    Genes Dev.

    (1997)
  • A.S. Nimnual

    Coupling of Ras and Rac guanosine triphosphatases through the Ras exchanger Sos

    Science

    (1998)
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