Nickolai Dulin, Ph.D.

Signaling Mechansisms by G Protein Coupled Receptors (GPCR)

Research Summary

My laboratory studies the mechanisms of G protein-mediated signal transduction, as they relate to gene expression, cell growth and survival. We focus on the signaling induced by the vasoactive agonists, such as endothelin-1 (ET1) and extracellular ATP, which are relevant to cardiovascular, pulmonary and renal physiology.  The goal is to dissect the role of various heterotrimeric G proteins, small GTPases and protein kinases in activation of gene transcription by ET1 or ATP in vascular smooth muscle cells. Serum response factor (SRF) – a transcription factor that controls expression of smooth muscle-specific proteins – is of particular interest to our lab. The complex mechanism of SRF regulation and smooth muscle gene expression by ET1 and ATP is an important part of these studies.

Regulators of G protein Signaling (RGS) – is another, yet closely related, focus of our laboratory.  The established function of RGS proteins is to bind and inactivate the alpha subunits of heterotrimeric G proteins. 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.  A long isoform of RGS3, PDZ-RGS3, can interact with Ephrin B – a transmembrane ligand for the ephrin B receptors implicated in cell-cell communication.  Another splice variant of RGS3, SRB-RGS, binds steroid receptors, such as estrogen receptors.  Elucidation of the new functions of RGS3 isoforms 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.