Robert J. Lefkowitz

Bio: Robert J. Lefkowitz is an academic researcher from Howard Hughes Medical Institute. The author has contributed to research in topics: Receptor & G protein-coupled receptor. The author has an hindex of 214, co-authored 860 publications receiving 147995 citations. Previous affiliations of Robert J. Lefkowitz include University of Nice Sophia Antipolis & University of Stuttgart.

Regulation of Mitogen-Activated Protein Kinase Pathways by Catecholamine Receptors

Abstract: Publisher Summary Until recently little has been known about the mechanisms of mitogenic signal transduction employed by receptors that couple to heterotrimeric G-proteins (GRs). These receptors participate in the regulation of cell proliferation in both physiological and pathophysiological states, and in cellular transformation in some, mostly neuroendocrine, human tumors. GRs that mediate cellular responses to a variety of humoral, endothelium-, or platelet-derived substances have been found to rapidly stimulate the mitogen-activated protein kinase (ERK1/2) pathway, a major point of convergence for signals regulating cell growth and differentiation. The best understood pathway of ERK1/2 activation is that mediated by growth factor receptors that possess intrinsic ligand-stimulated tyrosine kinase activity (RTK), such as the receptor for epidermal growth factor (EGF). To understand the mechanisms whereby GRs mediate growth regulatory signals, the mechanisms whereby several GRs, including the α 1 B AR and α 2 A AR, stimulate ERK1/2 activity in transiently transfected COS-7 and Chinese hamster ovary (CHO) cell model systems has been studied. In these cells, clear heterogeneity exists between the mechanisms of ERK1/2 activation employed by receptors that signal via pertussis toxin-sensitive G i family proteins, such as α 2 A AR, and receptors that signal via pertussis toxininsensitive G q/11 family proteins, such as α 1 B AR.

INHIBITION OF beta ARK AND beta -ARRESTIN

Abstract: beta -adrenergic receptor kinase ( beta ARK) and beta -arrestin function in the homologous or agonist-activated desensitization of G-protein coupled receptors. Both beta ARK-2 and beta -arrestin-2 isoforms are highly enriched in and localized to the cilia and dendritic knobs of the olfactory receptor neurons where the initial events of olfactory signal transduction occur as well as being localized to spermatids. Administration of neutralizing antibodies to beta ARK-2 and beta -arrestin-2 enhances the response to odorants and attenuates desensitization.

Regulation of the Adenylate Cyclase Signalling Pathway: Potential Role for the Phosphorylation of the Catalytic Unit by Protein Kinase A and Protein Kinase C

Abstract: We have investigated the phosphorylation of the pure catalytic unit of adenylate cyclase by cyclic AMP-dependent protein kinase (PKA) and Ca2+/phospholipid-dependent protein kinase (PKC). The catalytic unit of adenylate cyclase from bovine striatum was purified to apparent homogeneity by sequential affinity chromatography on forskolin-Sepharose and wheat germ aggulutinin-agarose to a specific activity of 1.5 μmol.mg-1.min-1. The enzyme migrates as a single band of M ~160,000 on sodium dodecyl sulfate-polyacrylamide electrophoresis gels and co-elutes with adenylate cyclase activity on steric-exclusion HPLC. The purified catalytic unit can be co-reconstituted with purified β2-adrenergic receptor and stimulatory guanine nucleotide regulatory protein (GS) resulting in their functional coupling. The enzyme can be phosphorylated by both PKA and PKC up to 0.9 mol of phosphate/mol of enzyme. Phosphorylation of the catalytic unit by PKA reduces the Gpp(NH)p-stimulated activity of the enzyme by 30% when co-reconstituted with GS, whereas PKC-phosphorylation of the enzyme enhances this activity by 25%. These results suggest that hormone-sensitive adenylate cyclase systems may be regulated in vivo by PKA- and PKC-dependent phosphorylation of their catalytic units.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans

Abstract: Experimental introduction of RNA into cells can be used in certain biological systems to interfere with the function of an endogenous gene Such effects have been proposed to result from a simple antisense mechanism that depends on hybridization between the injected RNA and endogenous messenger RNA transcripts RNA interference has been used in the nematode Caenorhabditis elegans to manipulate gene expression Here we investigate the requirements for structure and delivery of the interfering RNA To our surprise, we found that double-stranded RNA was substantially more effective at producing interference than was either strand individually After injection into adult animals, purified single strands had at most a modest effect, whereas double-stranded mixtures caused potent and specific interference The effects of this interference were evident in both the injected animals and their progeny Only a few molecules of injected double-stranded RNA were required per affected cell, arguing against stochiometric interference with endogenous mRNA and suggesting that there could be a catalytic or amplification component in the interference process

How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

Abstract: The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)