Protein Phosphorylations As a Mode of Insulin Action

Avruch, Joseph; Nemenoff, Raphael A.; Pierce, Mark; Kwok, Yan; Blackshear, Perry J.

doi:10.1007/978-1-4684-4874-0_16

Cited by 51 publications

(68 citation statements)

References 117 publications

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“…These purified receptor preparations exhibited insulinstimulated protein kinase activity which catalysed phosphorylation of both the f-subunit and exogenous substrates like casein, histones and synthetic tyrosinecontaining peptides. In contrast with the partially purified receptor, the phosphorylation occurred exclusively on tyrosine residues in highly purified receptors under basal conditions, and the insulin stimulatory action was accounted for by a several-fold increase in phosphotyrosine (Avruch et al, 1982;Petruzzelli et al, 1982Petruzzelli et al, , 1984Gazzano et al, 1983;Kasuga et al, 1983a;Roth & Cassell, 1983;. Thus, the tyrosine kinase is a constituent of the insulin receptor, whereas the serine kinase is non-covalently associated with the receptor (Fig.…”

Section: Vol 235mentioning

confidence: 97%

“…Even at 4°C, the phosphorylation was rapid; the 32P content of the receptor reached half-maximal level by 5 min and maximum after about 20 min (Zick et al, 1983c). As with the EGF-stimulated phosphorylation of the EGF receptor (Carpenter et al, 1979;Pike et al, 1984), Mn2+ was the most potent cation in augmenting the insulin-stimulated phosphorylation ofthe insulin receptor (Avruch et al, 1982;Petruzzelli et al, 1984;White et al, 1984;Zick et al, 1983c;Pike et al, 1984). The effect of Mn2+ was maximal at concentrations above 2 mm and constant up to 10 mM (Pike et al, 1984), but showed a complex relationship with the ATP concentration (see below).…”

Section: Vol 235mentioning

confidence: 98%

“…Subsequently, insulin-stimulated phosphorylation of the f-subunit of insulin receptor was demonstrated in cell-free systems using [y-32P]ATP in solubilized and partially purified receptor preparations from rat liver ( Fig. 3) and human placenta, and analysis of phosphoaminoacids showed predominant labelling of phosphotyrosine and to a smaller degree of phosphoserine (Kasuga et al, 1982b,;Van Obberghen et al, 1983: Avruch et al, 1982Petruzzelli et al, 1982;Roth & Cassell, 1983;. In intact cells phosphoaminoacid analysis of the phosphorylated fisubunit of insulin receptors showed phosphoserine, phosphothreonine and phosphotyrosine under basal conditions.…”

Section: Vol 235mentioning

confidence: 99%

“…Recently, a promising discovery was made by the demonstration that the insulin receptor is an insulinsensitive protein kinase (Kasuga et al, 1982a;Van Obberghen & Kowalski, 1982;Avruch et al, 1982;Petruzzelli et al, 1982). This novel observation is of interest for our understanding of insulin-regulated processes, since it is now recognized that covalent phosphorylation-dephosphorylation of proteins is a mechanism whereby many cellular functions are regulated by hormones and neurotransmitters (Denton et al, 1981;Cohen, 1982;Houslay, 1981).…”

Section: Introductionmentioning

confidence: 99%

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Protein kinase activity of the insulin receptor

Gammeltoft¹,

Obberghen²

1986

Biochemical Journal

139

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The insulin receptor is an integral membrane glycoprotein (Mr approximately 300,000) composed of two alpha-subunits (Mr approximately 130,000) and two beta-subunits (Mr approximately 95,000) linked by disulphide bonds. This oligomeric structure divides the receptor into two functional domains such that alpha-subunits bind insulin and beta-subunits possess tyrosine kinase activity. The amino acid sequence deduced from cDNA of the single polypeptide chain precursor of human placental insulin receptor revealed that alpha- and beta-subunits consist of 735 and 620 residues, respectively. The alpha-subunit is hydrophilic, disulphide-bonded, glycosylated and probably extracellular. The beta-subunit consists of a short extracellular region which links the alpha-subunit through disulphide bridges, a hydrophobic transmembrane region and a longer cytoplasmic region which is structurally homologous with other tyrosine kinases like the src oncogene product and EGF receptor kinases. The cellular function of insulin receptors is dual: transmembrane signalling and endocytosis of hormone. The binding of insulin to its receptor on the cell membrane induces transfer of signal from extracellular to cytoplasmic receptor domains leading to activation of cell metabolism and growth. In addition, hormone-receptor complexes are internalized leading to intracellular proteolysis of insulin, whereas receptors are recycled to the membrane. These phenomena are kinetically well-characterized, but their molecular mechanisms remain obscure. Insulin receptor in different tissues and animal species are homologous in their structure and function, but show also significant differences regarding size of alpha-subunits, binding kinetics, insulin specificity and receptor-mediated degradation. We suggest that this heterogeneity of receptors may be linked to the diversity in insulin effects on metabolism and growth in various cell types. The purified insulin receptor phosphorylates its own beta-subunit and exogenous protein and peptide substrates on tyrosine residues, a reaction which is insulin-sensitive, Mn2+-dependent and specific for ATP. Tyrosine phosphorylation of the beta-subunit activates receptor kinase activity, and dephosphorylation with alkaline phosphatase deactivates the kinase. In intact cells or impure receptor preparations, a serine kinase is also activated by insulin. The cellular role of two kinase activities associated with the insulin receptor is not known, but we propose that the tyrosine- and serine-specific kinases mediate insulin actions on metabolism and growth either through dual-signalling or sequential pathways.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Vol 235mentioning

confidence: 97%

Section: Vol 235mentioning

confidence: 98%

Section: Vol 235mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Protein kinase activity of the insulin receptor

Gammeltoft¹,

Obberghen²

1986

Biochemical Journal

139

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“…Inhibition of PTK activity by Zn*+ was reported for tyrosine phosphorylation of the epidermal growth factor receptor [28] and autophosphorylation of the insulin receptor which was completely blocked by 10 PM Zn*+ [29]. In contrast, Avruch et al [30] could not demonstrate an inhibitory effect of Zn*+ upon insulin receptor tyrosine phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Zn²⁺ enhances protein tyrosine kinase activity of human platelet membranes

Fındık

Presek

1988

FEBS Letters

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In human platelet membranes enhanced tyrosine phosphorylation of certain proteins was observed when Zn2+ instead of Mg2+ or Mn2+ was used as a divalent cation for the kinase reaction. An enhanced level of phosphate incorporation into tyrosine residues occurred into a 68 kDa polypeptide besides the 45 kDa and 105 kDa proteins. Preincubation of platelet membranes with TBR‐IgG showed a concentration‐dependent inhibition of the phosphorylation of the 45, 68 and 105 kDa proteins. Moreover, pp60c‐src, representing the major protein tyrosine kinase activity in platelets, was found to be stimulated by Zn2+. The data, thus, support the assumption that pp60c‐src kinase is responsible for Zn2+ stimulated tyrosine phosphorylation.

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Phosphatidylinositol turnover and transformation of cells by Abelson murine leukaemia virus.

Fry¹,

Gebhardt²,

Parker³

et al. 1985

The EMBO Journal

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The transforming protein of the Abelson murine leukaemia virus encodes a protein-tyrosine kinase. Previously, we have shown that in Abelson-transformed cells, the Abelson kinase regulates the phosphoserine content of ribosomal protein S6. Phorbol 12-myristate 13-acetate (TPA), which activates protein kinase C, induces the phosphorylation of S6 at the same five phosphopeptides as found in S6 isolated from Abelsontransformed cells. We have investigated three models whereby the Abelson kinase might regulate S6 phosphorylation via the activation of protein kinase C. First, the Abelson kinase could phosphorylate protein kinase C on tyrosine. However, we do not detect significant amounts of phosphotyrosine in protein kinase C in vivo. Second, it has been suggested that proteintyrosine kinases might phosphorylate phosphatidylinositol. This could increase the intracellular levels of diacylglycerol and thereby activate protein kinase C. Our data strongly suggest that direct phosphorylation of phosphatidylinositol by the Abelson protein-tyrosine kinase has no physiological role. Third, an indirect activation of protein kinase C may occur via an increase in the rate of phosphoinositide breakdown. We have found that phosphoinositide breakdown appears to be constitutively activated in Abelson-transformed cells. The implications of these observations are discussed with regard to S6 phosphorylation and the mechanism of Abelson-induced transformation.

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Protein Phosphorylations As a Mode of Insulin Action

Cited by 51 publications

References 117 publications

Protein kinase activity of the insulin receptor

Protein kinase activity of the insulin receptor

Zn²⁺ enhances protein tyrosine kinase activity of human platelet membranes

Phosphatidylinositol turnover and transformation of cells by Abelson murine leukaemia virus.

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Protein Phosphorylations As a Mode of Insulin Action

Cited by 51 publications

References 117 publications

Protein kinase activity of the insulin receptor

Protein kinase activity of the insulin receptor

Zn2+ enhances protein tyrosine kinase activity of human platelet membranes

Phosphatidylinositol turnover and transformation of cells by Abelson murine leukaemia virus.

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Zn²⁺ enhances protein tyrosine kinase activity of human platelet membranes