The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

Abstract

Recent discoveries have suggested the concept that intracellular signals are the sum of multiple, site-specified subsignals, rather than single, homogeneous entities. In the context of cancer, searching for compounds that selectively block subsignals essential for tumor progression, but not those regulating ''house-keeping'' functions, could help in producing drugs with reduced side effects compared to compounds that block signaling completely. The Ras-ERK pathway has become a paradigm of how space can differentially shape signaling. Today, we know that Ras proteins are found in different plasma membrane microdomains and endomembranes. At these localizations, Ras is subject to site-specific regulatory mechanisms, distinctively engaging effector pathways and switching-on diverse genetic programs to generate different biological responses. The Ras effector pathway leading to ERKs activation is also under strict, space-related regulatory processes. These findings may open a gate for aiming at the Ras-ERK pathway in a spatially restricted fashion, in our quest for new anti-tumor therapies.

Differential Regulation of RasGAPs in Cancer

“…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.…”

“…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. 19,[41][42][43] Most of the current knowledge on Ras isoform localization is based on ectopic expression of tagged Ras isoforms, either utilizing fluorescent proteins or short sequence motifs to target Ras isoforms to specific localizations at the cell surface or to endomembranes.…”

“…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. 19,[41][42][43] Most of the current knowledge on Ras isoform localization is based on ectopic expression of tagged Ras isoforms, either utilizing fluorescent proteins or short sequence motifs to target Ras isoforms to specific localizations at the cell surface or to endomembranes. Limited sensitivity of currently available technology is still impeding verification of the majority of these findings for endogenous H-, K-, and N-Ras.…”

“…Current models suggest that active Ras recruits regulators and effectors in small (<15 nm) signaling platforms. 19,[41][42][43] Electron microscopy and single-particle tracking studies showed activated H-and K-Ras to become transiently immobile, possibly to recruit downstream effectors, such as Raf and MAPK. [41][42][43] Similarly, once the Ras binding domain of p120GAP is recruited to the membrane, it is transiently immobile to interact with H-and K-Ras-GTP.…”

“…19,[41][42][43] Electron microscopy and single-particle tracking studies showed activated H-and K-Ras to become transiently immobile, possibly to recruit downstream effectors, such as Raf and MAPK. [41][42][43] Similarly, once the Ras binding domain of p120GAP is recruited to the membrane, it is transiently immobile to interact with H-and K-Ras-GTP. 54 Given that some full-length GAPs act differently compared to their GAP domains, 15 it is still to be determined if this mechanism also applies for fulllength p120GAP or other GAPs.…”