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Susan F. Steinberg, M.D.
Professor of Pharmacology and Medicine in the Center for Molecular Therapeutics
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Research
Summary
My research focuses on the signal transduction that mediate the cardiac actions of G protein-coupled receptors for catecholamines as well as thrombin. The unifying goals of our studies are to identify novel signaling mechanisms that contribute to cardiac cell growth and apoptosis (particularly in the context of heart failure syndromes). There currently are three major projects in the laboratory:
MECHANISMS UNDERLYING BETA-ADRENERGIC RECEPTOR SUBTYPE-SPECIFIC FUNCTION IN CARDIOMYOCYTES. My laboratory has been at the forefront of studies identifying distinct signaling pathways for cardiomyocyte beta1- and beta2-adrenergic receptors. Contrary to the traditional teaching that beta1- and beta2-receptors signal in a similar fashion through the Gs-cAMP second messenger pathway in heterologous expression systems, our studies have identified distinct actions for beta1- and beta2-receptor subtypes (including a cAMP-independent pathway for inotropic support by beta2-receptors) in the heart. Distinct beta-adrenergic receptor subtype function has important implications for the acute modulation of contractile function and the long-term modulation of cardiac muscle cell biology (with implication for the pathogenesis and therapy of clinical heart failure). Ongoing studies are designed to elucidate the molecular and cellular mechanisms that govern beta-receptor subtype action, with a particular focus on the role of membrane subdomains (variably described as lipid rafts or caveolae) as a mechanism to impose specificity in signaling through spatial compartmentation of receptor complexes.
THROMBIN RECEPTOR ACTIONS IN CARDIOMYOCYTES. Our studies implicate cardiomyocytes as targets for the cellular actions of thrombin and other serine proteases. We have demonstrated that cardiomyocytes express several members of the protease-activated receptor (PAR) family and that the prototypical thrombin receptor (PAR-1) contributes to cardiac remodeling by inducing cardiomyocyte hypertrophy and cardiac fibroblast proliferation. Ongoing studies focus on the distinct molecular determinants for thrombin receptor actions in the heart, with a particular emphasis on PAR-1 signaling through EGFR transactivation pathways.
PROTEIN KINASE C (PKC) DELTA REGULATION AND ACTIONS IN CARDIOMYOCYTES. My laboratory has maintained a long-standing interest in PKC isoform functions in the heart. PKC isoforms are targets of G protein-coupled receptor signaling pathways and they are implicated in the regulation of cardiac contractile function, ischemic preconditioning, and structural remodeling of the heart. Our recent studies identify a novel mechanism involving tyrosine phosphorylation of PKC-delta (one member of the PKC family of enzymes) by Src family kinases. This provides a mechanism to activate PKC-delta in a manner that alters its co-factor requirements and substrate specificity during oxidative stress. The precise molecular determinants and consequences of PKC-delta tyrosine phosphorylation, and in particular the impact of this regulatory mechanism on PKC-delta-dependent phosphorylation of myofibrillar proteins, are the subject of ongoing studies. Other studies identify a role for phospho-tyrosine residues on PKC-delta as docking sites for other proteins; studies to expose the consequences of kinase-independent actions of PKC-delta (as a scaffold – taking advantage of tissue culture and genetically altered mouse models) are ongoing.
http://www.cumc.columbia.edu/dept/cmt/participants/bios/steinberg.shtml
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Selected Publications:
1. Rybin VO, Xu X, Lisanti MP, and Steinberg SF.Differential targeting of ß-adrenergic receptor subtypes and adenylyl cyclase to cardiomyocyte caveolae. J Biol Chem
275:41447-41457, 2000.
2. Steinberg SF and Brunton LL. Compartmentalization of G-protein-mediated signal transduction components in cardiomyocyte. Annual Review of Pharmacology and Toxicology
41:751-773, 2001.
3. Sabri A, Guo J, Elouardighi H, Darrow AL, Andrade-Gordon P, and. Steinberg SF.Mechanisms of protease-activated receptor-4 actions in cardiomyocytes; role of Src tyrosine kinase. J Biol Chem
278:11714-11720, 2003.
4. Rybin VO, Sabri A, Short J, Braz JC, Molkentin JD, and. Steinberg SF.Cross regulation of nPKC isoform function in cardiomyocytes: Role of PKC-epsilon in activation loop phosphorylations and PKC-delta ?in hydrophobic motif phosphorylations. J Biol Chem
278:14555-14564, 2003.
5. Rybin VO, Guo J, Sabri A, Elouardighi H, Schaefer E, and Steinberg SF.Stimulus-specific differences in PKCd localization and activation mechanisms in cardiomyocytes. J Biol Chem
279:19350-19361, 2004.
6. Steinberg SF. The cardiovascular actions of protease-activated receptors. Mol Pharm
67:2-11, 2005.
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