Insulin Stimulates the Phosphorylation of the 95,000-Dalton Subunit of Its Own Receptor

Kasuga, Masato; Karlsson, F. Anders; Kahn, C. Ronald

doi:10.1126/science.7031900

Cited by 1,126 publications

(441 citation statements)

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“…This was first demonstrated in rat hepatoma cells and human IM9 lymphoblasts (Kasuga et al, 1982a) and later in freshly isolated rat hepatocytes (Van Obberghen & Kowalski, 1982). In these experiments, cells were preincubated with [32P]Pi to label cellular ATP, solubilized in detergent, and the glycoproteins purified on wheat-germ-agglutinin-agarose.…”

Section: Vol 235mentioning

confidence: 99%

“…This applies to all tissues investigated so far, including liver (Kasuga et al, 1982b;Van Obberghen et al, 1983), adipose tissue (Haring et al, 1982;Velicelebi & Aiyer, 1984), muscle (Burant et al, 1984;Haring et al, 1984b;Le Marchand-Brustel et al, 1985), placenta (Petruzzelli et al, 1982;Roth & Cassell, 1983;, lymphocytes (Grunberger et al, 1984a), erythrocytes (Grigorescu et al, 1983), fibroblasts , brain cortex (Gammeltoft et al, 1984a;Rees-Jones et al, 1984), and various cell lines like IM 9 lymphoblasts (Kasuga et al, 1982a), 3T3-L1 adipocytes (Petruzzelli et al, 1982), hepatoma cells (Kasuga et al, 1982a, c;White et al, 1984) and insulinoma cells . Thus, the insulin-sensitive kinase is a general feature of the insulin receptor.…”

Section: Role Of Receptor Phosphorylation In Insulin Actionmentioning

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: 99%

Section: Role Of Receptor Phosphorylation In Insulin Actionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Protein kinase activity of the insulin receptor

Gammeltoft¹,

Obberghen²

1986

Biochemical Journal

139

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“…I~RO~UCTION The insulin receptor is a multimeric complex composed of two major subunits: the a-subunit (A.& 130~) containing the insulin binding site [1,2], and the &subunit (Mr 95000) containing a protein kinase activity leading to a selfphosphorylation of the receptor in the presence of insulin [3,4]. In addition to these 2 major components, a MI 45000 polypeptide has also been observed [5,6] and is thought to represent a proteolytic fragment of the &subunit [6].…”

mentioning

confidence: 99%

Immunoprecipitation of insulin receptors by antibodies against Class 1 antigens of the murine H‐2 major histocompatibility complex

et al. 1983

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“…Although these enzymes have been implicated in assembly of myosin into filaments, in actin-activated ATPase activity (Scholey et al, 1980;Adelstein & Eisenberg, 1980), in insulin action (Kasuga et al, 1982), in neoplastic transformation (Levinson et al, 1978;Collett et al, 1980) and in protein synthesis (Ochoa & de Haro, 1979), the physiological role of these kinases is still obscure. A common feature of these enzymes is their preference for acidic proteins such as casein and phosvitin as substrates, but not for histones and protamines.…”

Section: Introductionmentioning

confidence: 99%

A cyclic AMP-independent protein kinase from Candida albicans

Roy

Datta

1986

Biochemical Journal

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A cyclic AMP-independent protein kinase which phosphorylates casein was purified to homogeneity from Candida albicans by affinity and ion-exchange chromatography. This protein kinase exhibits maximal activity with casein as substrate and is not stimulated by cyclic AMP or cyclic GMP. The Mr of the purified enzyme is 115,000, as determined by h.p.l.c. It migrates as a single band on gel electrophoresis and has three non-identical subunits, of Mr 44,000, 28,500 and 26,000, as determined by SDS/polyacrylamide-gel electrophoresis. This enzyme is insensitive to heparin, but is inhibited by polyamines. Furthermore, it is sensitive to thermal denaturation and to thiol reagents.

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Insulin Stimulates the Phosphorylation of the 95,000-Dalton Subunit of Its Own Receptor

Cited by 1,126 publications

References 24 publications

Protein kinase activity of the insulin receptor

Protein kinase activity of the insulin receptor

Immunoprecipitation of insulin receptors by antibodies against Class 1 antigens of the murine H‐2 major histocompatibility complex

A cyclic AMP-independent protein kinase from Candida albicans

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