Activation of multiple small GTPases in the Ras and Rho families promotes the proliferation and migration of non-small cell lung carcinoma (NSCLC) cells, which contributes to NSCLC tumorigenesis and metastasis. Surprisingly little is known about how small GTPases are activated in NSCLC cells to promote tumorigenesis and metastasis. Our research indicates that the unique guanine nucleotide exchange factor known as SmgGDS is a major regulator of small GTPase activity in NSCLC. SmgGDS uniquely activates multiple small GTPases in the Ras and Rho families. We previously reported that SmgGDS is expressed at high levels in NSCLC tumors and stimulates the proliferation and migration of NSCLC cells. We recently discovered that NSCLC cells express several forms of SmgGDS. Our results support the model that different forms of SmgGDS promote post-translational processing of the small GTPases K-Ras, Rac1, RhoA, Rap1A, and Rap1B. This model will be tested in the following aims.
Aim1 : Define the expression of different forms of SmgGDS in NSCLC tumors from patients and in NSCLC cell lines.
Aim 2 : Determine which form of SmgGDS and which of the small GTPases that interact with SmgGDS contribute the most to NSCLC cell proliferation, migration, tumorigenesis, and experimental metastasis.
Aim 3 : Characterize how different forms of SmgGDS regulate the activity, post-translational processing, and subcellular localization of different small GTPases in NSCLC. This research will define the unique ability of SmgGDS to regulate the activities of K-Ras, Rac1, RhoA, Rap1A, and Rap1A in NSCLC, and will help determine the therapeutic potential of these proteins in lung cancer.
Lung cancer cells make a group of proteins called "small GTPases". When these small GTPases are activated in lung cancer cells, they induce the lung cancer cells to proliferate and migrate, which promotes tumorigenesis and metastasis. Our laboratory is investigating how these small GTPases are activated in lung cancer, because this information will help us design new ways to stop the activation of small GTPases, and thereby stop lung cancer tumorigenesis and metastasis. We found that a protein called SmgGDS activates small GTPases in lung cancer cells and is made in high amounts in lung tumors from patients. Our proposed research will define how SmgGDS activates different small GTPases in lung cancer. This research may discover how small GTPases are activated in lung cancer and thus may identify new approaches to stop these proteins from promoting lung cancer tumorigenesis and metastasis.
|Schuld, Nathan J; Vervacke, Jeffrey S; Lorimer, Ellen L et al. (2014) The chaperone protein SmgGDS interacts with small GTPases entering the prenylation pathway by recognizing the last amino acid in the CAAX motif. J Biol Chem 289:6862-76|
|Hauser, Andrew D; Bergom, Carmen; Schuld, Nathan J et al. (2014) The SmgGDS splice variant SmgGDS-558 is a key promoter of tumor growth and RhoA signaling in breast cancer. Mol Cancer Res 12:130-42|
|Schuld, Nathan J; Hauser, Andrew D; Gastonguay, Adam J et al. (2014) SmgGDS-558 regulates the cell cycle in pancreatic, non-small cell lung, and breast cancers. Cell Cycle 13:941-52|
|Williams, Carol L (2013) A new signaling paradigm to control the prenylation and trafficking of small GTPases. Cell Cycle 12:2933-4|
|Ntantie, Elizabeth; Gonyo, Patrick; Lorimer, Ellen L et al. (2013) An adenosine-mediated signaling pathway suppresses prenylation of the GTPase Rap1B and promotes cell scattering. Sci Signal 6:ra39|
|Nithipatikom, Kasem; Gomez-Granados, Ana Doris; Tang, Alan T et al. (2012) Cannabinoid receptor type 1 (CB1) activation inhibits small GTPase RhoA activity and regulates motility of prostate carcinoma cells. Endocrinology 153:29-41|
|Gastonguay, Adam; Berg, Tracy; Hauser, Andrew D et al. (2012) The role of Rac1 in the regulation of NF-ýýB activity, cell proliferation, and cell migration in non-small cell lung carcinoma. Cancer Biol Ther 13:647-56|
|Cheng, Gang; Lopez, Marcos; Zielonka, Jacek et al. (2011) Mitochondria-targeted nitroxides exacerbate fluvastatin-mediated cytostatic and cytotoxic effects in breast cancer cells. Cancer Biol Ther 12:707-17|
|Nithipatikom, Kasem; Brody, Daniel M; Tang, Alan T et al. (2010) Inhibition of carcinoma cell motility by epoxyeicosatrienoic acid (EET) antagonists. Cancer Sci 101:2629-36|
|Rao, V Ashutosh; Klein, Sarah R; Bonar, Spencer J et al. (2010) The antioxidant transcription factor Nrf2 negatively regulates autophagy and growth arrest induced by the anticancer redox agent mitoquinone. J Biol Chem 285:34447-59|
Showing the most recent 10 out of 11 publications