The laboratory research focuses on the regulation of the interaction among G protein coupled receptor (GPCR), G proteins and RGS (Regulators of G Protein Signaling) proteins in cardiovascular disease and prostate cancer. GPCR/G protein-mediated signaling controls many cellular processes. G proteins stimulate intracellular signaling proteins (effectors) when they bind GTP in response to receptor; signaling ends when bound GTP is hydrolyzed. RGS proteins can act as GTPase-Activating Proteins (GAPs) and may accelerate the deactivation of G proteins by 1000-fold. It is important to understand how RGS proteins can act as tightly regulated modulators and integrators of multiple GPCR/G protein signaling pathways. This elucidation will not only help us understand the roles RGS proteins play in physiology and diseases, but also has the potential to provide crucial information for RGS-target drug development.
Prostate cancer is the most common cancer in American men and acquisition of androgen independence by prostate cancer is the key problem of prostate cancer progression. Several lines of evidence suggest that androgen-independent activation of androgen receptor (AR) is one underlying mechanism of androgen independence. We recently reported that RGS2, a member of the RGS protein superfamily, inhibits androgen-independent AR signaling in prostate cancer cells. We are currently investigating the role of dysregulation of RGS2 in androgen-independent progression of prostate cancer by using both in vitro and in vivo models. Our studies will significantly advance understanding of how dysregulation of RGS proteins causes GPCR-mediated androgen-independent AR activation, thus contributing to prostate cancer progression to androgen-independent disease. Such knowledge will ultimately aid in the design of novel therapeutic approaches for hormone-refractory prostate cancers.
Metastasis, the hormone stimulated migration of cancer cells from the primary tumor and their subsequent invasion and proliferation in healthy tissues, is the chief cause of mortality in prostate cancer. Some of the hormones that stimulate metastasis act via GPCRs. Mounting evidence suggests that Rac-dependent directed cell migration plays a critical role in prostate cancer metastasis. We recently found that migration of prostate cancer cells was enhanced by P-Rex1, a Rac-specific activator that is stimulated by Gi-coupled GPCRs. P-Rex1 expression was correlated with the metastatic potential of established human prostate cancer cell lines, and metastatic human prostate cancer specimens expressed significantly higher levels of P-Rex1 protein compared to matched normal prostate tissues and localized prostate tumors. We are now attempting to identify the factors that trigger prostate cancer migration and are investigating the molecular mechanisms underlying prostate cancer metastasis. Our studies could lead to the development of novel anti-metastasis strategies for preventing and halting prostate cancer progression.
New Research Interest in Asthma
One of the most important therapies in asthma is the use of "beta agonists," which open the airway by binding to proteins called "Beta2-receptors," found on the surface of airway muscle cells, thereby causing the muscles to relax. Yet, other members of this receptor family trigger airway muscle cells to contract, instead of relax, but there is a certain protein that normally blocks the activity of these receptors, preventing the contractions of airway muscles. Dr. Tu previously has found evidence that these protective proteins may be reduced in asthma, thereby allowing airway muscle cells to contract excessively, so he will test the hypothesis that this is a cause of asthma which, if true, could provide a new pathway for the development of therapies.
For link to American Asthma Foundation Research Grant Awardees, click here
For full Scientific Abstract, click here