New Insights into the Role of SmgGDS as a Major Integrator of Signaling by Ras and Rho Family Members in Cancer

Abstract

Small GTPases in the Ras and Rho families are major participants in the signaling cascades that promote malignancy. Defining how these signaling cascades are integrated can lead to new approaches to inhibit cancer development and progression. The chaperone protein SmgGDS (gene name RAP1GDS1) is perhaps the best example of a protein partner that integrates signaling by multiple small GTPases, because SmgGDS binds many Ras and Rho family members that have a C‐terminal polybasic region (PBR), including K‐Ras4B, Rap1, RhoA, RhoC, Rac1, Rac1b, DiRas1, and DiRas2. Interactions with small GTPases contribute to the well‐documented ability of SmgGDS to promote breast, lung, and prostate cancer, but our mechanistic understanding of how these interactions specifically promote malignancy is not well‐defined. We previously reported that SmgGDS controls the prenylation and membrane trafficking of newly synthesized GTPases, which promotes oncogenic signaling by the small GTPases. These results indicate that SmgGDS is a major regulator of small GTPases. We are currently investigating the alternative (but not mutually exclusive) possibility that small GTPases are major regulators of SmgGDS. In this presentation, we will discuss our recent discoveries suggesting that the binding of different small GTPases directs SmgGDS to specific subcellular compartments, where SmgGDS participates in unique signaling cascades that promote malignancy. We recently discovered that nuclear trafficking of SmgGDS causes SmgGDS to accumulate in the nucleolus and bind the nucleolar protein upstream binding factor (UBF). Our results indicate that nuclear SmgGDS protects cells from nucleolar stress and promotes cell proliferation by regulating the DREAM complex, which is a transcription factor complex that controls expression of cell cycle proteins. To begin to define whether small GTPases can regulate these functions of SmgGDS, we tested different small GTPases for their ability to control the subcellular localization and protein interactions of SmgGDS. We found that DiRas1, which is a GTPase that acts as a tumor suppressor, diminishes binding of SmgGDS to UBF and other small GTPases, and reduces nucleolar accumulation of SmgGDS, resulting in SmgGDS localizing throughout the nucleoplasm. Interestingly, RhoA expression also diminishes binding of SmgGDS to UBF, but this effect seems to be caused by RhoA diminishing nucleocytoplasmic trafficking of SmgGDS, resulting in nuclear exclusion of SmgGDS. Expression of other GTPases, such as K‐Ras4B and Rap1A, did not detectably alter SmgGDS interaction with UBF. Our discovery that specific GTPases can direct SmgGDS to different subcellular locations suggests that the interaction of PBR‐containing small GTPases with SmgGDS not only promotes unique signaling cascades mediated by the GTPases, but also promotes unique signaling cascades mediated by SmgGDS. Thus, SmgGDS might serve as both an upstream regulator, and a downstream effector, of the multiple PBR‐containing small GTPases that bind SmgGDS. These findings provide further rationale to develop therapeutic strategies targeting SmgGDS in cancer.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.