Increasing complexity of Ras signaling

Abstract

The initial discovery that ras genes endowed retroviruses with potent carcinogenic properties and the subsequent determination that mutated ras genes were present in a wide variety of human cancers, prompted a strong suspicion that the growth-promoting actions of mutated Ras proteins contribute to their aberrant regulation of growth stimulatory signaling pathways. In 1993, a remarkable convergence of experimental observations from genetic analyses of Drosophila, S. cerevisiae and C. elegans as well as biochemical and biological studies in mammalian cells came together to de®ne a clear role for Ras in signal transduction. What emerged was an elegant linear signaling pathway where Ras functions as a relay switch that is positioned downstream of cell surface receptor tyrosine kinases and upstream of a cytoplasmic cascade of kinases that included the mitogen-activated protein kinases (MAPKs). Activated MAPKs in turn regulated the activities of nuclear transcription factors. Thus, a signaling cascade where every component between the cell surface and the nucleus was de®ned and conserved in worms,¯ies and man. This was a remarkable achievement in our e orts to appreciate how the aberrant function of Ras proteins may contribute to the malignant growth properties of the cancer cell. However, the identi®cation of this pathway has proven to be just the beginning, rather than the culmination, of our understanding of Ras in signal transduction. Instead, we now appreciate that this simple linear pathway represents but a minor component of a very complex signaling circuitry. Ras signaling has emerged to involve a complex array of signaling pathways, where cross-talk, feedback loops, branch points and multi-component signaling complexes are recurring themes. The simplest concept of a signaling cascade, where each component simply relays the same message to the next, is clearly not the case. In this review, we summarize our current understanding of Ras signal transduction with an emphasis on new complexities associated with the recognition and/or activation of cellular e ectors, and the diverse array of signaling pathways mediated by interaction between Ras and Ras-subfamily proteins with multiple e ectors.

Induction of erythroid differentiation by inhibition of Ras/ERK pathway in a Friend murine leukemia cell line

“…Using this cell line, we established two subclones which express either an activated (12V) or a dominant-negative (17N) mutant of H-ras oncogene (Feig and Cooper, 1988;Campbell et al, 1998) by using a tetracycline (Tet)-regulated expression system (Tet-o system) (Gossen and Bujard, 1992;Shockett et al, 1995). In these clones (named ras17N/SKTtet and ras12V/SKTtet, respectively), strong induction of the transgene expression was observed both at the levels of mRNA and protein after withdrawal of Tet from the medium (Figure 1a).…”

“…Since MAPK cascades are known to function downstream of Ras in various systems (Campbell et al, 1998), we examined whether MAPK activities are A B Figure 1 Regulated expression of ras12V and ras17N genes in SKTtet cells. (a) Total RNA extracted from ras 12V/SKTtet cells (lanes 1, 2) or ras17N/SKTtet cells (lanes 3, 4) incubated in the absence (lanes 1, 3) or presence (lanes 2, 4) of 1 mg/ml Tet for 24 h. The RNA samples were analysed by RNA blot hybridization with ras (upper panels) and b-actin (middle panels) probe.…”

“…The Ras family proteins are known to transduce signals through a series of target molecules including two cytoplasmic protein serine/threonine kinases, Raf-1 and PI3K (Campbell et al, 1998). Binding to the plasma membrane-associated Ras proteins enables Raf-1 kinase to phosphorylate its substrate MEK (a MAPK kinase) which in turn phosphorylates the 42/ 44-KDa species of MAPK (ERK).…”

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

“…We sought to determine how Ras mediates the mitogenic e ects of TSH in a manner that allows for maintenance of the di erentiated phenotype. Ras activates multiple downstream e ectors including Raf-1, PI3K and RalGDS (Marshall, 1996;Campbell et al, 1998). The contribution of individual Ras e ectors to the inhibition of thyroid di erentiation has not been established.…”

The Angiogenic Switch Molecule, Secreted FGF-Binding Protein, an Indicator of Early Stages of Pancreatic and Colorectal Adenocarcinoma

“…The K-ras pathway mediates the cellular response to extracellular signals, such as growth factors, cytokines, and hormones that regulate cell proliferation, differentiation, and apoptosis (18). Mutation of the ras proto-oncogene has been detected in various human cancers, including 95% of pancreatic cancers and up to 50% of large bowel adenocarcinomas (19)(20)(21).…”