The effects of mutant Ras proteins on the cell signalome

Abstract

The genetic alterations in cancer cells are tightly linked to signaling pathway dysregulation. Ras is a key molecule that controls several tumorigenesis-related processes, and mutations in RAS genes often lead to unbiased intensification of signaling networks that fuel cancer progression. In this article, we review recent studies that describe mutant Ras-regulated signaling routes and their cross-talk. In addition to the two main Ras-driven signaling pathways, i.e., the RAF/MEK/ERK and PI3K/AKT/mTOR pathways, we have also collected emerging data showing the importance of Ras in other signaling pathways, including the RAC/PAK, RalGDS/Ral, and PKC/PLC signaling pathways. Moreover, microRNA-regulated Ras-associated signaling pathways are also discussed to highlight the importance of Ras regulation in cancer. Finally, emerging data show that the signal alterations in specific cell types, such as cancer stem cells, could promote cancer development. Therefore, we also cover the up-to-date findings related to Ras-regulated signal transduction in cancer stem cells.

Keywords: Mutant Ras protein; Phosphorylation; Signal transduction; Tumorigenesis.

Fig. 1

Schematic representation of Ras proteins. The GTPase domain consists of six β-strands (red labeled) and five α-helices (blue labeled). Three inter -β-strand and α-helix loops are highlighted, i.e., the P-loop, the switch I, and the switch II regions. The P-loop binds the beta phosphate of guanosine phosphates. The switch I and switch II regions undergo conformational changes during GTP-GDP hydrolysis and determine the interactions of Ras partner proteins. The positions of the three most frequent codon mutations are labeled with red letters, i.e., the glycines at codons 12 and 13 and the glutamine at codon 61. The two threonines at positions 144 and 148 (labeled with orange letters) can be phosphorylated by GSK3β kinase and organize the ubiquitination of Ras to regulate degradation. Each Ras protein has an isoform-specific hypervariable region (HVR) at the C-terminus that can be post-translationally modified through palmitoylation, farnesylation, acetylation, methylation, or prenylation. The sequences of the four HVR regions of K-Ras4B, K-Ras4A, H-Ras, and N-Ras (depicted in blue) determine the PM and lipid raft localization of Ras. The pie charts show the G12, G13, and Q61 mutation frequencies in the given isoforms

Fig. 2

Schematic representation of the mechanism leading to constitutively active forms of mutant Ras. The transition from inactive GDP-bound to active GTP-bound Ras is regulated by several factors, including GEFs and GAPs. Oncogenic mutant Ras proteins could remain in a prolonged active form. Mutations in Ras can result in an accelerated intrinsic GDP/GTP exchange rate or impairment of its intrinsic hydrolytic activity. In addition to changing the intrinsic enzymatic activity of Ras, oncogenic Ras mutations can also alter its sensitivity to GAP and GEF activity

Fig. 3

Signaling networks involved in Ras-driven oncogenesis. This figure summarizes the core members of the signaling pathways radiating from mutant Ras. The two robust Ras-driven signaling routes are the RAF/MEK/ERK and PI3K/AKT pathways, which regulate diverse cellular processes, particularly cell proliferation and cell survival regulation, respectively. Other Ras activation-dependent signaling routes are less studied. The TIAM1/RAC/PAK pathway primarily controls cytoskeleton rearrangement in certain cells, and the RalGDS/Ral pathway mostly influences membrane trafficking. The NORE1/RASSF1/MST signaling pathway is a regulator of cell death processes. Mutant Ras can also mediate signaling via PLC/PKC molecules to influence Ca+-dependent signaling in cancer cells