SmgGDS-558 regulates the cell cycle in pancreatic, non-small cell lung, and breast cancers

Abstract

Oncogenic mutation or misregulation of small GTPases in the Ras and Rho families can promote unregulated cell cycle progression in cancer. Post-translational modification by prenylation of these GTPases allows them to signal at the cell membrane. Splice variants of SmgGDS, named SmgGDS-607 and SmgGDS-558, promote the prenylation and membrane trafficking of multiple Ras and Rho family members, which makes SmgGDS a potentially important regulator of the cell cycle. Surprisingly little is known about how SmgGDS-607 and SmgGDS-558 affect cell cycle-regulatory proteins in cancer, even though SmgGDS is overexpressed in multiple types of cancer. To examine the roles of SmgGDS splice variants in the cell cycle, we compared the effects of the RNAi-mediated depletion of SmgGDS-558 vs. SmgGDS-607 on cell cycle progression and the expression of cyclin D1, p27, and p21 in pancreatic, lung, and breast cancer cell lines. We show for the first time that SmgGDS promotes proliferation of pancreatic cancer cells, and we demonstrate that SmgGDS-558 plays a greater role than SmgGDS-607 in cell cycle progression as well as promoting cyclin D1 and suppressing p27 expression in multiple types of cancer. Silencing both splice variants of SmgGDS in the cancer cell lines produces an alternative signaling profile compared with silencing SmgGDS-558 alone. We also show that loss of both SmgGDS-607 and SmgGDS-558 simultaneously decreases tumorigenesis of NCI-H1703 non-small cell lung carcinoma (NSCLC) xenografts in mice. These findings indicate that SmgGDS promotes cell cycle progression in multiple types of cancer, making SmgGDS a valuable target for cancer therapeutics.

The Tumor-suppressive Small GTPase DiRas1 Binds the Noncanonical Guanine Nucleotide Exchange Factor SmgGDS and Antagonizes SmgGDS Interactions with Oncogenic Small GTPases

“…There are two predominant isoforms of SmgGDS, SmgGDS-607 and SmgGDS-558, which differ by one armadillo domain (5). Recent studies have demonstrated that SmgGDS-558 plays a more significant role than SmgGDS-607 in activating RhoA in breast cancer cells, despite lower levels of endogenous SmgGDS-558 protein (6,7). In addition, SmgGDS promotes RhoA-mediated NF-B transcriptional activity (6,8,9), which is critical to cancer cell growth and proliferation (10).…”

GEF mechanism revealed by the structure of SmgGDS-558 and farnesylated RhoA complex and its implication for a chaperone mechanism

“…In complexes II and III, the electron density of RhoA PBR (amino acids 181-189) was observed, but the density was so poor that only main-chain atoms were modeled. In addition, the P loop and its flanking region (amino acids [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] were disordered in complexes II and III ( Fig. 1 B-D and SI Appendix, Fig.…”

“…SmgGDS interacts with various small GTPases possessing a Cterminal polybasic region (PBR) upstream of the CaaX motif in a hypervariable region (HVR) (5,6,(11)(12)(13). SmgGDS is overexpressed in nonsmall cell lung carcinoma (14,15), prostate cancer (16), breast cancer (15,17), and pancreatic cancer (15). SmgGDS is a unique architectural GEF that is entirely composed of armadillo-repeat motifs (ARMs) (18).…”

Immunoproteasome Deficiency Protects in the Retina after Optic Nerve Crush

“…To test for statistical significance between treatment groups, data was analyzed by one-way analysis of variance (ANOVA) followed by a Dunnett’s Multiple Comparison Post-hoc test, or by a Pearson Correlation test using Graphpad PRISM version 5.00 for Windows, GraphPad Software (San Diego California, USA, www.graphpad.com ) as described previously [ 40 , 41 ]. A Dixon’s Q-Test was performed to identify and eliminate outliers from the data.…”