SmgGDS: An Emerging Master Regulator of Prenylation and Trafficking by Small GTPases in the Ras and Rho Families

Abstract

Newly synthesized small GTPases in the Ras and Rho families are prenylated by cytosolic prenyltransferases and then escorted by chaperones to membranes, the nucleus, and other sites where the GTPases participate in a variety of signaling cascades. Understanding how prenylation and trafficking are regulated will help define new therapeutic strategies for cancer and other disorders involving abnormal signaling by these small GTPases. A growing body of evidence indicates that splice variants of SmgGDS (gene name RAP1GDS1) are major regulators of the prenylation, post-prenylation processing, and trafficking of Ras and Rho family members. SmgGDS-607 binds pre-prenylated small GTPases, while SmgGDS-558 binds prenylated small GTPases. This review discusses the history of SmgGDS research and explains our current understanding of how SmgGDS splice variants regulate the prenylation and trafficking of small GTPases. We discuss recent evidence that mutant forms of RabL3 and Rab22a control the release of small GTPases from SmgGDS, and review the inhibitory actions of DiRas1, which competitively blocks the binding of other small GTPases to SmgGDS. We conclude with a discussion of current strategies for therapeutic targeting of SmgGDS in cancer involving splice-switching oligonucleotides and peptide inhibitors.

Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth

“…We prioritized a list of candidate genes according to the probability of their protein products interacting with KRAS, their mRNA expression in mouse models of oncogenic KRAS G12D -driven lung cancer, and the probability of their protein products interacting with other RAS GTPases (Figure 1b-c, Figure S1a-d) 10,21 . We selected 13 proteins that represent diverse aspects of RAS biology, including RAS paralogs (HRAS, NRAS -which were supported by the identification of paralogspecific peptides), RAS regulators (RASGRF2, RAP1GDS1) 22,23 , a RAS farnesyltransferase (FNTA) 24,25 , and RAS effectors (RAF1, RGL2) 26,27 , as well as several other proteins whose functions in RAS signaling are understudied. Analysis of human lung adenocarcinoma genomic data showed that while most of these candidate genes trend to be more often amplified in human adenocarcinoma, NRAS, HRAS, and ALDH1A1 also have deep genomic deletions (Figure S1e) 28 .…”

Crucial roles of Rab22a in endosomal cargo recycling

“…Interestingly Rab22a‐NeoF1, an abnormal fusion protein in osteosarcoma, has a novel protein–protein interaction with small G protein guanine dissociation stimulator 607 (SmgGDS‐607) 73 . Because this interaction sequences RhoA out of SmgGDS‐607, a GDI of RhoA, Rab22a‐NeoF1 can be considered as a GDF of RhoA 74 …”

“…73 Because this interaction sequences RhoA out of SmgGDS-607, a GDI of RhoA, Rab22a-NeoF1 can be considered as a GDF of RhoA. 74…”

RHO GTPase family in hepatocellular carcinoma

“…Furthermore, membrane association is a prerequisite of RHO GTPase activation, whereas their ability to anchor at the membranes depends on the presence of the prenyl group. Splice variants of SmgGDS are major regulators of the prenylation of RHO family members [ 145 ]. However, statins can increase SmgGDS expression via targeting HMG CoA reductase pathway and thus diminishing lipid modifications needed by Rho GTPases to suppress their activation [ 146 , 147 ].…”