Insulin receptors in rat brain: insulin stimulates phosphorylation of its receptor β‐subunit

Gammeltoft, Steen; Kowalski, Aline; Fehlmann, Max; Obberghen, Emmanuel Van

doi:10.1016/0014-5793(84)80879-0

Cited by 52 publications

(18 citation statements)

References 9 publications

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“…Sa) whereas that of the fl-subunit (Mr -94000) is similar (Fig. Sb) (Yip et al, 1980;Heidenreich et al, 1983;Gammeltoft et al, 1984a;Rees-Jones et al, 1984). The binding properties show striking differences in comparison with other cell types, because negatively co-operative interactions are absent (Gammeltoft et al, 1984b;Van Schravendijk et al, 1984) and the insulin specificity is different (Gammeltoft et al, 1984b(Gammeltoft et al, , 1985b.…”

Section: Heterogeneity Of Insulin Receptorsmentioning

confidence: 75%

“…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%

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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: Heterogeneity Of Insulin Receptorsmentioning

confidence: 75%

Section: Role Of Receptor Phosphorylation In Insulin Actionmentioning

confidence: 99%

Protein kinase activity of the insulin receptor

Gammeltoft¹,

Obberghen²

1986

Biochemical Journal

139

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“…After ultracentrifugation (100 000 g for 1 h at 4°C) the supernatant was applied to a WGA-agarose column. The glycoproteins were eluted with N-acetylglucosamine (0.3 M), and used for binding and protein kinase assays Gammeltoft et al, 1984).…”

Section: Methodsmentioning

confidence: 99%

Insulin-like growth factor I in cultured rat astrocytes: expression of the gene, and receptor tyrosine kinase.

et al. 1987

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Gene expression, receptor binding and growth-promoting activity of insulin-like growth factor I (IGF I) was studied in cultured astrocytes from developing rat brain. Northern blot analysis of poly(A)+ RNAs from astrocytes revealed an IGF I mRNA of 1.9 kb. Competitive binding and receptor labelling techniques revealed two types of IGF receptor in astroglial cells. Type I IGF receptors consist of a-subunits (Mr 130 000) which bind IGF I with significantly higher affinity than IGF 11, and fl-subunits (Mr 94 000) which show IGF Isensitive tyrosine kinase activity. Type II IGF receptors are monomers (Mr 250 000) which bind IGF H with three times higher affinity than IGF I. Both types of IGF receptor recognize insulin weakly. DNA synthesis measured by cellular thymidine incorporation was stimulated 2-fold by IGF I and IGF H. IGF I was more potent than IGF H, and both were significantly more potent than insulin. Our findings suggest that IGF I is synthesized in fetal rat astrocytes and acts as a growth promoter for the same cells by activation of the type I IGF receptor tyrosine kinase. We propose that IGF I acts through autocrine or paracrine mechanisms to stimulate astroglial cell growth during normal brain development.

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“…It can be a result of differences in structure of receptors originating from various tissues. The brain receptor is a bit smaller molecule and this distinction arises from differences in N-linked glycosylation (Unger et al, 1991a;Gammeltoft et al, 1984). However, besides described differences in the characteristics of brain and liver membrane receptors, in the light of the present paper, it can be stated both their ability to changing in various circumstances and the regulatory effect of a diet on them.…”

Section: Resultsmentioning

confidence: 62%

High-carbohydrate and high-protein diets alter liver and brain insulin receptors in rats

Maćkowiak¹,

Ładoń²,

Nogowski³

et al. 1993

J. Anim. Feed Sci.

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Insulin receptors of liver and brain plasma membranes were investigated in rats kept on standard (S), high-carbohydrate (HC) and high-protein (HP) diets. Both liver and brain show similar tendency to reduce number of high affinity receptors and their affinity to the hormone in rats fed a HP diet. After a HC diet the effects seem to be opposite. Animals show nearly the same number of receptors as in the control group but the affinity of insulin binding to liver -but not brain plasma membranes is enhanced.

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Insulin receptors in rat brain: insulin stimulates phosphorylation of its receptor β‐subunit

Cited by 52 publications

References 9 publications

Protein kinase activity of the insulin receptor

Protein kinase activity of the insulin receptor

Insulin-like growth factor I in cultured rat astrocytes: expression of the gene, and receptor tyrosine kinase.

High-carbohydrate and high-protein diets alter liver and brain insulin receptors in rats

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