Divergent Roles of CAAX Motif-signaled Posttranslational Modifications in the Regulation and Subcellular Localization of Ral GTPases

Abstract

Background:The highly related small GTPases RalA and RalB exhibit distinct functions in cancer cell processes. Results: Posttranslational modifications signaled by the C-terminal CAAX motif contribute to Ral isoform differences in subcellular localization, activation, and protein stability. Conclusion: Modifications catalyzed by RCE1, ICMT, and protein palmitoyl acyltransferase cause Ral isoform-specific functional consequences. Significance: Inhibitors of CAAX motif modifications will have complex consequences on Ral GTPase regulation.

Focus on the glycerophosphocholine pathway in choline phospholipid metabolism of cancer

“…RAS protein function requires several posttranslational modifications . The posttranslational modification of RAS starts with the addition of farnesylpyrophosphate to the cysteine residue of the carboxy‐terminal tetrapeptide CAAX motif . In this motif, C is a cysteine, A is an aliphatic amino acid (ie, leucine, isoleucine or valine) and X is a terminal residue (ie, methionine, serine, leucine or glutamine) .…”

“…The posttranslational modification of RAS starts with the addition of farnesylpyrophosphate to the cysteine residue of the carboxy‐terminal tetrapeptide CAAX motif . In this motif, C is a cysteine, A is an aliphatic amino acid (ie, leucine, isoleucine or valine) and X is a terminal residue (ie, methionine, serine, leucine or glutamine) . This is followed by the addition of palmitate to one or two cysteine residues immediately upstream of the CAAX sequence .…”

Plasma membrane phosphatidylinositol 4-phosphate and 4,5-bisphosphate determine the distribution and function of K-Ras4B but not H-Ras proteins

“…Although there is a paper suggesting that the Ral pathway is originated from the Golgi (51), it is widely accepted that active PM-bound Ras proteins can activate cell proliferation through the Ral-TBK1 pathway (52). Additionally, we can find examples in the literature that palmitoylation could also occurs on further cysteine residues away from the terminal cysteine within the C-terminal tail domain, which strengthen the PM anchoring of Ral, and prevent the detachment of this molecule from the PM after PM PPIns depletion, as could be seen in the case of the H-Ras protein (53,54).…”

Inhibitors of Ras–SOS Interactions

“…Am ajor stumbling block in designing such aR as-isoform-specific drugi st he high structural similarity among the catalytic domains of the isoforms. However,i ti sh oped that cases in which the hypervariable region (HVR) also contributes to the interactions, [72][73][74][75] as in calmodulin, [76] can attain isoform selectivity with small-molecule inhibitors. An alternate strategy might involvei ntracellular antibodies.…”