Nickolai Dulin, Ph.D.

Signaling Mechansisms by G Protein Coupled Receptors (GPCR)

Research Summary

Uncontrolled cell proliferation and survival underlines the pathogenesis of cancer. Protein kinase A (PKA) controls cell proliferation and survival through phosphorylation of multiple target proteins. My laboratory focuses on identification of novel targets of PKA and understanding how their phosphorylation affects cell growth. We have reported that PKA phosphorylates and regulates the activity of glycogen synthase kinase 3 (GSK3), beta-catenin and serum response factor (SRF) – the proteins known to control mitogenesis. Employing phosphoproteomics approach, we have recently identified a number of other novel PKA substrates, whose function is currently under investigation.

Regulators of G protein Signaling (RGS) proteins represent another subject of our studies.  The established function of RGS proteins is to bind and inactivate the alpha subunits of heterotrimeric G proteins and as a result, to regulate the signaling mediated by various G protein-coupled receptors. However, increasing evidence suggests that this is not the only function of RGS proteins, as they can bind other targets.  We have found that one of the RGS family members, RGS3, can interact with the phosphoserine-binding protein 14-3-3, which regulates many signaling molecules implicated in cell growth and survival. Our recent studies also point to the transducers of TGF-beta signaling, Smad transcription factors as novel targets of RGS3. Understanding the crosstalk between G protein- and TGF-beta signaling through RGS3 and how this affect cell growth, differentiation and migration is the goal of this study.

Selected Papers

Dulin NO, Alexander LD, Harwalkar S, Falk JR and Douglas JG. (1998). Phospholipase A2-mediated activation of mitogen-activated protein kinase by angiotensin II. Proc. Natl. Acad. Sci. USA. 95:8098-8102.

Dulin NO, Sorokin A and Douglas JG. (1998). Arachidonate-induced tyrosine phosphorylation of epidermal growth factor receptor and Shc-Grb2-Sos association. Hypertension 32:1089-1093.

Dulin NO, Sorokin A, Reed E, Elliott S, Kehrl GH, and Dunn MJ. (1999). RGS3 inhibits G protein-mediated signaling via translocation to the membrane and binding to Ga11. Mol. Cell. Biol. 19:714-723.

Dulin NO, Pratt P, Voyno-Yasenetskaya T and Dunn MJ. (2000). Regulator of G protein signaling RGS3T is localized to the nucleus and induces apoptosis. J. Biol. Chem. 275:21317-21323.

Dulin NO, Niu J, Browning DD, Ye R and Voyno-Yasenetskaya T. (2001). Cyclic AMP - independent activation of protein kinase A by vasoactive peptides. J. Biol. Chem. 276:20827-20830.

Dulin NO, Orlov SN, Kitchen CM, Voyno-Yasenetskaya T and Miano J. (2001). G-protein-coupled-receptor activation of the smooth muscle calponin gene. Biochem. J. 357:587-592.

Niu J, Scheschonka A, Druey K, Davis A, Reed E, Kolenko V, Bodnar R, Voyno-Yasenetskaya T, Du W, Kehrl J and Dulin NO. (2002). RGS3 interacts with 14-3-3 via the N-terminal region distinct from RGS domain. Biochem. J. 365: 677-684.

Davis A, Hogarth K, Fernandes D, Solway J, Niu J, Kolenko V, Browning D, Miano JM, Orlov SN, Dulin NO. (2003). Functional significance of protein kinase A activation by endothelin-1 and ATP: negative regulation of SRF-dependent gene expression by PKA. Cell. Signal. 15:597-604.

Hogarth DK, Sandbo N, Taurin S, Kolenko V, Miano JM, and Dulin NO. (2004). Dual role of PKA in the phenotypic modulation of vascular smooth muscle cells by extracellular ATP. Am. J. Phys. Cell Physiol. 287:C449-C456.

Sandbo N, Qin Y, Taurin S, Hogarth DK, Kreutz B, Dulin NO. (2005). Regulation of SRF-dependent gene expression by proteasome inhibitors. Mol. Pharmacol. 67:789-797.

Taurin S, Sandbo N, Qin Y, Browning D, and Dulin NO. (2006). Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase. J. Biol. Chem. 281(15):9971-9976.

Taurin S., Hogarth K, Sandbo N, Yau DM, Dulin NO. Gbg-mediated activation of PKA by endothelin-1 promotes vascular smooth muscle cell hypertrophy through inhibition of glycogen synthase kinase-3.  J. Biol. Chem. 2007, 282(27):19518-25.

Yau DM., Sethakorn N., Taurin S., Kregel S., Sandbo N., Camoretti-Mercado B., Sperling AI, Dulin NO. Regulation of Smad-mediated gene transcription by RGS3. Mol. Pharlmacol. 2008, 73:1356-61.

Taurin S., Sandbo N, Yau DM, Sethakorn N, Dulin NO. Phosphorylation of beta-catenin by PKA promotes ATP-induced proliferation of vascular smooth muscle cells. Am. J. Physiol. Cell Physiol. 2008, 294(5):C1169-74.