Ras proteins: paradigms for compartmentalised and isoform-specific signalling

Abstract

Ras GTPases mediate a wide variety of cellular processes by converting a multitude of extracellular stimuli into specific biological responses including proliferation, differentiation and survival. In mammalian cells, three ras genes encode four Ras isoforms (H-Ras, K-Ras4A, KRas4B and N-Ras) that are highly homologous but functionally distinct. Differences between the isoforms, including their post-translational modifications and intracellular sorting, mean that Ras has emerged as an important model system of compartmentalised signalling and membrane biology. Ras isoforms in different subcellular locations are proposed to recruit distinct upstream and downstream accessory proteins and activate multiple signalling pathways. Here, we summarise data relating to isoform specific signalling, its role in disease and the mechanisms promoting compartmentalised signalling. Further understanding of this field will reveal the role of Ras signalling in development, cellular homeostasis and cancers and may suggest new therapeutic approaches.

Differential Regulation of RasGAPs in Cancer

“…[1][2][3] In addition, knockout mice revealed essential roles for K-Ras in development, while H-and N-Ras appeared dispensible for mouse embryogenesis. [16][17][18][19] Along these lines, defects in human development have recently been associated with Ras isoform-specific functions. [19][20][21] The different magnitude of oncogenic Ras isoform signaling further supports signal specificity of Ras isoforms.…”

“…[16][17][18][19] Along these lines, defects in human development have recently been associated with Ras isoform-specific functions. [19][20][21] The different magnitude of oncogenic Ras isoform signaling further supports signal specificity of Ras isoforms. Although there is some controversy about the differential ability of Ras isoforms to activate downstream effectors, some studies suggested that H-Ras strongly activates the PI3K/Akt pathway, while K-Ras is a more potent activator of the Raf/MAPK pathway.…”

“…This includes the different localization and lateral segregation of activated Ras isoforms in different microdomains of the plasma membrane but also Ras isoform-specific signaling from different endomembranes. 19,[41][42][43] The stabilization of microdomains containing different Ras isoforms could then provide platforms for the differential recruitment of GAPs and other Ras regulators/ effectors, leading to the formation of signal-and compartment-specific protein complexes. 19,[41][42][43] It would go beyond the scope of this review to summarize the literature on the microlocalization of Ras isoforms, and we refer the reader to more detailed reviews from others on this topic.…”

K-Ras4B phosphorylation at Ser181 is inhibited by calmodulin and modulates K-Ras activity and function

“…Their differential localization determines specific Ras signaling output, becoming more accessible to a specific set of effectors and regulators (Hancock, 2003;Prior et al, 2003;Matallanas et al, 2006;Omerovic et al, 2007). Although we have only begun to dissect Ras isoformspecific signaling, it has been described that N-Ras is a major activator of the Raf-1/MEK/ERK cascade, whereas K-Ras is an important regulator of the PI3K/ AKT pathway (Hamilton et al, 2001;Liao et al, 2006).…”

Cell surface dynamics – how Rho GTPases orchestrate the interplay between the plasma membrane and the cortical cytoskeleton

“…The Ras GTPases, which include the three well-known oncoproteins H-Ras, K-Ras and R-Ras, the Rap proteins and a few other GTPases, have key roles in cell survival, proliferation and differentiation (reviewed by Goldfinger, 2008;Johnson and Chen, 2012). The functional differences among the members of this family depend, in part, on their different subcellular distribution (Omerovic et al, 2007).…”