Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The acute effects of insulin, adenosine, and isoproterenol on the activity, subcellular distribution, and phosphorylation state of the GLUT4 glucose transporter isoform were investigated in rat adipocytes under conditions carefully controlled to monitor changes in cAMP-dependent protein kinase (A-kinase) activity. In contrast to GLUT1, which has not been shown to be phosphorylated even when cells are exposed to any of the above agents, GLUT4 was partially phosphorylated (0.1-0.2 mol/mol) when the activity of the A-kinase was suppressed, and remained unchanged in response to insulin. Isoproterenol elicited a 64% inhibition of insulin-stimulated glucose transport activity in the absence, but not the presence, of adenosine receptor agonists. However, in either the presence or the absence of agonists, A-kinase was activated as assessed by examining the phosphorylation of the major adipocyte A-kinase substrate, perilipin. Similarly, under either condition, phosphorylation of GLUT4 was enhanced 1.4-fold in the intracellular membranes, but no significant change was observed in the plasma membrane. In the absence of adenosine receptor agonists, isoproterenol exerted a small (14%) but significant inhibition of the insulin-induced translocation of GLUT4 but had no effect on the translocation of GLUT1. Thus, changes in the phosphorylation state and/or subcellular distribution of GLUT4 cannot account for the inhibition of insulin-stimulated glucose activity induced by isoproterenol.
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PMID:Phosphorylation state of the GLUT4 isoform of the glucose transporter in subfractions of the rat adipose cell: effects of insulin, adenosine, and isoproterenol. 176 64

The lipid fraction ("fat cake") of rat epididymal adipocytes contains a prominent phosphoprotein (62 kDaapp by sodium dodecyl sulfate-polyacrylamide gel electrophoresis) that is multiply phosphorylated by cAMP-dependent protein kinase in vivo, at which point it migrates as a 65/67-kDaapp doublet by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and is by far the most heavily radiolabeled protein in the cell. Western blot analysis of various tissues with immunopurified antibodies purified from antisera raised against the 62-kDa species suggests that the protein is specific for adipocytes. This protein, which we term perilipin, is found in differentiated cultured 3T3-L1 adipocytes, but not in their precursor 3T3-L1 fibroblasts. Immunocytochemical studies with specific antiserum shows that the perilipin is closely associated with the periphery of lipid storage droplets in cultured adipocytes. Given its adipocyte specificity, acute regulation by hormones, and subcellular location, we speculate that perilipin plays a role in the specialized lipid storage function of adipocytes.
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PMID:Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets. 204 Jun 38

The major cAMP-dependent protein kinase (A-kinase) substrate in adipocytes is perilipin, a protein found exclusively at the surface of the lipid storage droplets. Using anti-perilipin serum, we have isolated two related classes of full-length coding cDNAs, designated perilipin A and B, from a rat adipocyte cDNA expression library. The two cDNAs derive from two mRNA species that arise by differential splicing. The mRNAs are predicted to encode perilipins A and B, proteins of 517 aa (56,870 Da) and 422 aa (46,420 Da), respectively, which share a common 406-aa N-terminal sequence. The predicted perilipin A contains peptides present in proteolytic digests of the purified 62-kDa form of perilipin from rat adipocytes, as well as the requisite consensus A-kinase phosphorylation sites. Like perilipin A, the B form is expressed in adipocytes and is associated with lipid storage droplets. Modeling of predicted secondary structures fails to reveal an underlying basis for the tenacious association of perilipins with lipid droplets. These proteins exhibit a significant sequence relationship (approximately 65% similarity through 105 aa) with only one other known protein, the adipocyte differentiation-related protein (ADRP). Like the perilipins, ADRP appears to be adipocyte-specific, which suggests that they interact in a related intracellular pathway. The molecular probes for perilipins A and B described here will permit detailed analyses of their functional role(s) in lipid metabolism.
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PMID:Isolation of cDNAs for perilipins A and B: sequence and expression of lipid droplet-associated proteins of adipocytes. 750 52

Steroidogenic cells store cholesteryl esters, precursors for steroid hormone synthesis, in intracellular lipid droplets. Cholesteryl ester hydrolysis is activated by protein kinase A and catalyzed by cholesteryl esterase. The esterase is similar, if not identical, to hormone-sensitive lipase in adipocytes where an analogous lipolytic mechanism occurs. Perilipins, proteins located exclusively at lipid droplet surfaces in adipocytes, are polyphosphorylated by protein kinase A in response to lipolytic stimuli, suggesting a role for these proteins in mediating lipid metabolism. The present study reveals that perilipins are associated with cholesteryl ester droplets in two steroidogenic cell lines: Y-1 adrenal cortical cells and MA-10 Leydig cells. The relative abundance of perilipin mRNAs and protein is much less in steroidogenic cells than in adipocytes. Like adipocytes, steroidogenic cells express perilipin A; additionally, the latter cells contain relatively abundant amounts of perilipin C, a protein that is not detectable in adipocytes by Western analysis. The data suggest a strong link between perilipins and lipid hydrolysis that is mediated by the hormone-sensitive lipase/cholesteryl esterase class of enzymes.
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PMID:Perilipins are associated with cholesteryl ester droplets in steroidogenic adrenal cortical and Leydig cells. 762 16

For several reasons it seems reasonable to suspect that perilipins participate in lipid hydrolysis. First, they are located at the lipid droplet surface, the presumed site of HSL and cholesteryl esterase action. Secondly, they are polyphosphorylated by PKA in concert with lipid hydrolysis. Finally, these proteins appear to be expressed primarily, if not solely, in adipocytes and steroidogenic cells, cells in which lipid hydrolysis is stimulated by cyclic AMP and mediated by HSL or cholesteryl esterase(s), whereas other cells that contain abundant neutral lipid depositions contain no perilipin [13]. Interestingly, these closely related hydrolases share no homology with other mammalian lipases [3]. Although such attributes provide a link between perilipin and lipid hydrolysis, we have no evidence that perilipins participate directly in, or are necessary for, lipid catabolism. The basis for the strong affinity between the perilipins and neutral lipids is unknown. Clearly, lipids and perilipins are tightly linked, as evidenced by selective targeting of epitope-tagged perilipin to lipid droplets and by the paradoxical appearance of lipid droplets in pre-adipocytes transfected with a sense perilipin A construct. Indeed, in differentiating adipocytes the earliest lipid depositions are associated with perilipins, and restriction of perilipin synthesis with anti-sense constructs may impede lipid formation and deposition. It remains to be determined if, in the normal course of events, perilipins are directed toward lipid depositions or if lipids are transported to perilipin foci. Whatever the temporal sequence, the result is that neutral lipids are encased in perilipin-bounded droplets.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Perilipin: unique proteins associated with intracellular neutral lipid droplets in adipocytes and steroidogenic cells. 856 27

Perilipins are a family of unique proteins intimately associated with the limiting surface of neutral lipid storage droplets in adipocytes and in steroidogenic cells. Lipid hydrolysis in these cells is initiated by cAMP, which leads to phosphorylation of hormone-sensitive lipase in adipocytes and cholesteryl esterase in steroidogenic cells by protein kinase A. Although the concurrent phosphorylation of perilipin by this kinase suggests a role for these proteins in lipid breakdown, a role for these proteins in lipid packaging or in maintaining the lipid droplet structure cannot be excluded.
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PMID:Perilipin: possible roles in structure and metabolism of intracellular neutral lipids in adipocytes and steroidogenic cells. 868 Apr 86

Brown adipose tissue contains both beta(1)- and beta(3)-adrenergic receptors (beta-ARs), and whereas both receptor subtypes can activate adenylyl cyclase, recent studies suggest that these subtypes have different pharmacological properties and may serve different signaling functions. In this study, primary brown adipocyte cultures were used to determine the role of beta-AR subtypes in mediating lipolysis and uncoupling protein-1 (UCP1) gene expression, elicited by the physiological neurohormone norepinephrine (NE). NE increased both lipolysis and UCP1 mRNA levels in brown adipocyte cultures; the beta(1)-receptor-selective antagonist CGP-20712A strongly antagonized the increase in UCP1 gene expression but had little effect on lipolysis. The beta(3)-receptor-selective agonist CL-316243 (CL) also increased lipolysis and UCP1 mRNA levels, yet CL was more potent in stimulating lipolysis than UCP1 gene expression. NE also increased the phosphorylation of cAMP response element-binding protein (CREB) and perilipin (PL), both of which are protein kinase A substrates that are differentially targeted to the nucleus and lipid droplets, respectively. beta(1)-receptor blockade inhibited NE-stimulated phosphorylation of CREB but not PL. The results suggest that beta-AR subtypes regulate different physiological responses stimulated by NE in brown adipocyte cultures in part by differentially transducing signals to subcellular compartments.
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PMID:Differential regulation of functional responses by beta-adrenergic receptor subtypes in brown adipocytes. 1040 68

The lipolytic reaction in adipocytes is one of the most important reactions in the management of bodily energy reserves, and dysregulation of this reaction may contribute to the symptoms of Type 2 diabetes mellitus. Yet, progress on resolving the molecular details of this reaction has been relatively slow. However, recent developments at the molecular level begin to paint a clearer picture of lipolysis and point to a number of unanswered questions. While HSL has long been known to be the rate-limiting enzyme of lipolysis, the mechanism by which HSL attacks the droplet lipids is not yet firmly established. Certainly, the immunocytochemical evidence showing the movement of HSL to the lipid droplet upon stimulation leaves little doubt that this translocation is a key aspect of the lipolytic reaction, but whether or not HSL phosphorylation contributes to the translocation, and at which site(s), is as yet unresolved. It will be important to establish whether there is an activation step in addition to the translocation reaction. The participation of perilipin A is indicated by the findings that this protein can protect neutral lipids within droplets from hydrolysis, but active participation in the lipolytic reaction is yet to be proved. Again, it will be important to determine whether mutations of serine residues of PKA phosphorylation sites of perilipins prevent lipolysis, and whether such modifications abolish the physical changes in the droplet surfaces that accompany lipolysis.
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PMID:On the control of lipolysis in adipocytes. 1084 61

The Perilipins are a family of intracellular neutral lipid droplet storage proteins that are responsive to acute protein kinase A-mediated, hormonal stimulation. Perilipin (Peri) expression appears to be limited to adipocytes and steroidogenic cells, in which intracellular neutral lipid hydrolysis is regulated by protein kinase A. We have isolated cDNA sets and overlapping genomic fragments of the murine Peri locus and mapped chromosomal location, transcription start sites, polyadenylylation sites, and intron/exon junctions. Data confirm that the Perilipins are encoded by a single-copy gene, with alternative and tissue-specific, mRNA splicing and polyadenylylation yielding four different protein species. The Perilipin proteins have identical approximately 22-kDa amino termini with distinct carboxyl terminal sequences of varying lengths. These genomic and transcriptional maps of murine Perilipin are also essential for evaluating presumptive endogenous and targeted mutations within the locus. The N-terminal identity region of the Perilipins defines a sequence motif, which we term PAT, that is shared with the ADRP and TIP47 proteins; additionally, the PAT domain may represent a novel, conserved pattern for lipid storage droplet (LSD) proteins of vertebrates and invertebrates alike. Comparative genomics suggest the presence of related LSD genes in species as diverse as Drosophila and Dictyostelium.
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PMID:The murine perilipin gene: the lipid droplet-associated perilipins derive from tissue-specific, mRNA splice variants and define a gene family of ancient origin. 1164 24

Perilipin (Peri) A is a phosphoprotein located at the surface of intracellular lipid droplets in adipocytes. Activation of cyclic AMP-dependent protein kinase (PKA) results in the phosphorylation of Peri A and hormone-sensitive lipase (HSL), the predominant lipase in adipocytes, with concurrent stimulation of adipocyte lipolysis. To investigate the relative contributions of Peri A and HSL in basal and PKA-mediated lipolysis, we utilized NIH 3T3 fibroblasts lacking Peri A and HSL but stably overexpressing acyl-CoA synthetase 1 (ACS1) and fatty acid transport protein 1 (FATP1). When incubated with exogenous fatty acids, ACS1/FATP1 cells accumulated 5 times more triacylglycerol (TG) as compared with NIH 3T3 fibroblasts. Adenoviral-mediated expression of Peri A in ACS1/FATP1 cells enhanced TG accumulation and inhibited lipolysis, whereas expression of HSL fused to green fluorescent protein (GFPHSL) reduced TG accumulation and enhanced lipolysis. Forskolin treatment induced Peri A hyperphosphorylation and abrogated the inhibitory effect of Peri A on lipolysis. Expression of a mutated Peri A Delta 3 (Ser to Ala substitutions at PKA consensus sites Ser-81, Ser-222, and Ser-276) reduced Peri A hyperphosphorylation and blocked constitutive and forskolin-stimulated lipolysis. Thus, perilipin expression and phosphorylation state are critical regulators of lipid storage and hydrolysis in ACS1/FATP1 cells.
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PMID:Modulation of hormone-sensitive lipase and protein kinase A-mediated lipolysis by perilipin A in an adenoviral reconstituted system. 1175 1


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