Protein kinase activity of the insulin receptor from muscle

Häring, Hans Ulrich; Machicao, Fausto; Kirsch, D.; Rinninger, Franz; Hölzl, J.; Eckel, J; Bachmann, W. E.

doi:10.1016/0014-5793(84)80947-3

Cited by 10 publications

(4 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…body mass index and insulin levels. Our results comparing IRK from non-obese Type 2 diabetic patients and non-obese control subjects, isolated as described earlier [190], may be summarized as follows. No difference in insulin binding was found.…”

Section: Irk In Insulin Target Tissues Of Type 2 Diabetic Patientsmentioning

confidence: 87%

“…It is speculated, that binding of insulin to its receptor induces a conformational change or a dimerization of receptor o~-subunits [55-59]. Very similar structural changes of the receptor molecule can be induced by cer- [180][181][182][183][184][185][186][187][188][189][190] pp 15 (cytoskel eton) . Following the idea that the unoccupied c~-subunit functions as an inhibitor of the [3-subunit [61] it seems possible that the insulin binding-induced conformational change of the o~-subunit is transduced to the 13-subunit and leads to relief from kinase inhibition H. U. H~ring: The insulin receptor (Fig.…”

Section: The Binding Step and Signal Transfer From The ~-To The [}-Snbunit: Increasing Evidence That Conformational Changes Of The ~Lsnbnmentioning

confidence: 99%

See 1 more Smart Citation

The insulin receptor: signalling mechanism and contribution to the pathogenesis of insulin resistance

Häring

1991

Diabetologia

131

View full text Add to dashboard Cite

The insulin receptor is a heterotetrameric structure consisting of two alpha-subunits of Mr 135 kilodalton on the outside of the plasma membrane connected by disulphide bonds to beta-subunits of Mr 95 kilodalton which are transmembrane proteins. Insulin binding to the alpha-subunit induces conformational changes which are transduced to the beta-subunit. This leads to the activation of a tyrosine kinase activity which is intrinsic to the cytoplasmatic domains of the beta-subunit. Activation of the tyrosine kinase activity of the insulin receptor represents an essential step in the transduction of an insulin signal across the plasma membrane of target cells. Signal transduction on the post-kinase level is not yet understood in detail, possible mechanisms involve phosphorylation of substrate proteins at tyrosine residues, activation of serine kinases, the interaction with G-proteins, phospholipases and phosphatidylinositol kinases. Studies in multiple insulin-resistant cell models have demonstrated that an impaired response of the tyrosine kinase to insulin stimulation is one potential mechanism causing insulin resistance. An impairment of the insulin effect on tyrosine kinase activation in all major target tissues of insulin, in particular the skeletal muscle was demonstrated in Type 2 (non-insulin-dependent) diabetic patients. There is no evidence that the impaired tyrosine kinase response in the skeletal muscle is a primary defect, however, it is likely that this abnormality of insulin signal transduction contributes significantly to the pathogenesis of the insulin-resistant state in Type 2 diabetes.

show abstract

Section: Irk In Insulin Target Tissues Of Type 2 Diabetic Patientsmentioning

confidence: 87%

Section: The Binding Step and Signal Transfer From The ~-To The [}-Snbunit: Increasing Evidence That Conformational Changes Of The ~Lsnbnmentioning

confidence: 99%

The insulin receptor: signalling mechanism and contribution to the pathogenesis of insulin resistance

Häring

1991

Diabetologia

131

View full text Add to dashboard Cite

show abstract

“…In the proteins, phosphoaminoacid analysis showed only phosphorylation on tyrosine residues. Among the synthetic peptides, even the dipeptide Tyr-Arg was a substrate, although with very high Km (Stadtmauer & Rosen, 1983 Kasuga et al (1982a-c), Van Obberghen et al (1983, Haring et al (1982Haring et al ( , 1984b, Velicelebi & Aiyer (1984), Burant et al (1984), Petruzzelli et al (1982, Roth & Cassell (1983), (1982b, 1983a,b), Van Obberghen et al (1983), Roth et al (1982, Petruzzelli et al (1984 Gazzano et al (1983, Kasuga et al (1983b), Pike et al (1984), Stadtmauer & Rosen (1983), Sadoul et al (1985), …”

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%

Protein kinase activity of the insulin receptor

Gammeltoft¹,

Obberghen²

1986

Biochemical Journal

139

View full text Add to dashboard Cite

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)

show abstract

Insulin receptor kinase defects in insulin‐resistant tissues and their role in the pathogenesis of NIDDM

Häring

Obermaier-Kusser

1989

Diabetes Metab. Rev.

View full text Add to dashboard Cite

Protein kinase activity of the insulin receptor from muscle

Cited by 10 publications

References 18 publications

The insulin receptor: signalling mechanism and contribution to the pathogenesis of insulin resistance

The insulin receptor: signalling mechanism and contribution to the pathogenesis of insulin resistance

Protein kinase activity of the insulin receptor

Insulin receptor kinase defects in insulin‐resistant tissues and their role in the pathogenesis of NIDDM

Contact Info

Product

Resources

About