scholarly journals Elevated protein tyrosine phosphatase activity and increased membrane viscosity are associated with impaired activation of the insulin receptor kinase in old rats

1994 ◽  
Vol 298 (2) ◽  
pp. 443-450 ◽  
Author(s):  
O Nadiv ◽  
M Shinitzky ◽  
H Manu ◽  
D Hecht ◽  
C T Roberts ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Receptor Kinase ◽  
Membrane Viscosity ◽  
Liver Membranes ◽  
Old Rats ◽  
Insulin Receptor Kinase

Insulin resistance is very common in the elderly, and may be associated with glucose intolerance or frank diabetes. In previous studies we demonstrated that insulin resistance in old Wistar rats is associated with decreased autophosphorylation and activation of the hepatic insulin receptor kinase (IRK) in vivo. We now show that this defect can be reproduced in vitro, where the extent of insulin-induced activation of IRK in liver membranes of old rats was decreased by approximately 50% compared with young controls. The defect could be largely abolished after solubilization of the membranes with Triton X-100. We also show that: (a) the viscosity of membranes from the old rats was significantly (P < 0.001, n = 4) higher (by 15%) compared with young controls; (b) incubation of plasma membranes from old animals with lecithin liposomes, which lowered their cholesterol levels, partially abolished the defect in IRK activation; and (c) Triton extracts of liver membranes prepared from old rats did not interfere with the activation of IRK derived from young controls. Additionally, non-membrane components did contribute to the development of this defect. We observed a significant (approximately 30%) (P < 0.001, n = 18) elevation of cytosolic protein tyrosine phosphatase (PTP) activity directed against the beta subunit of the insulin receptor in livers of old rats. No such elevation of PTP activity could be demonstrated with synthetic substrates. Our findings are consistent with a model in which increased membrane viscosity as well as enhancement of a cytosolic PTP activity both markedly inhibit the activation in vivo of the hepatic IRK in old animals.

Comparative modeling of the phosphatase and kinase domains of protein tyrosine phosphatase and insulin receptor kinase from Drosophila melanogaster (DPTP61fm), and a computational study of their mutual interactions

2002 ◽  
Vol 80 (2) ◽  
pp. 225-239 ◽  
Author(s):  
Sanchita Hati ◽  
Sudeep Bhattacharyya ◽  
James V Price ◽  
Alan S Tracey
Keyword(s):  
Hydrogen Bonding ◽  
Drosophila Melanogaster ◽  
Insulin Receptor ◽  
Protein Tyrosine Phosphatase ◽  
Computational Study ◽  
Tyrosine Phosphatase ◽  
Receptor Kinase ◽  
Protein Tyrosine ◽  
Insulin Receptor Kinase ◽  
High Degree

The components and functions of the insulin receptor kinase signaling pathway have been conserved in a broad range of Metazoa ranging from mammals to insects and nematodes. There is a high degree of sequence homology and functional similarity between the human insulin receptor kinase (IRK) and the drosophila (Drosophila melanogaster) form (DIRK) of this enzyme. Similarly, a high degree of homology exists between human protein tyrosine phosphatase 1B (PTP1B) (which directly regulates IRK) and its drosophila counterpart DPTP61F (DPTP). However, genetic and biochemical studies have yet to demonstrate that DPTP61F acts in the DIRK pathway. Comparative structural modeling techniques using the known structures of human IRK and PTP1B as templates have yielded structures for the drosophila enzymes. The derived structures confirm that there is a high level of structural conservation at the tertiary level. Association of the DIRK and DPTP enzymes with each other was then investigated with a view to ascertaining whether DIRK might be a substrate of the DPTP. Evaluation of the interaction surfaces, including hydrophobic patch, shape, hydrogen bonding, and electrostatic compatibility, strongly suggested that the drosophila insulin receptor is a substrate of the DPTP. The interaction surfaces of the human and drosophila enzymes are structurally similar, although changes in critical residues modify possible electrostatic and hydrogen-bonding interactions. This suggests that in the mixed systems, DPTP–IRK or PTP1B–DIRK, the kinase domain will be a comparatively poor substrate for phosphatase activity when compared with the native systems.Key words: protein tyrosine phosphatase, insulin receptor kinase, Drosophila melanogaster, comparative protein modeling, surface topology, interaction zone.

Effect of a high-fat-sucrose diet on in vivo insulin receptor kinase activation

1990 ◽  
Vol 259 (1) ◽  
pp. E111-E116 ◽  
Author(s):  
J. J. Boyd ◽  
I. Contreras ◽  
M. Kern ◽  
E. B. Tapscott ◽  
D. L. Downes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Kinase Activity ◽  
Insulin Binding ◽  
Receptor Kinase ◽  
High Fat ◽  
Glucose Injection ◽  
Insulin Receptor Kinase

Insulin-stimulated glucose uptake into muscle is depressed by high-fat-sucrose (HFS) feeding of rats. To investigate the mechanism of this insulin resistance, the in vivo activation of the insulin receptor kinase in liver and muscle of control and HFS-fed rats was determined. Rats were injected with glucose and insulin and killed 0, 5, 15, and 30 min after injection. Insulin binding was not changed in partially purified receptors from muscle of HFS rats. In control rats insulin receptor kinase activity was maximally stimulated threefold in liver at 5 min and fourfold in muscle at 15 min after insulin-glucose injection. The insulin-stimulated tyrosine kinase activity of receptors isolated from the liver of rats fed the HFS diet was decreased by 30% in comparison with the controls. In contrast, receptors isolated from muscle did not show any difference in basal or insulin-stimulated kinase activity between HFS-fed and control rats. Decreased in vivo activation of the insulin receptor kinase may be at least partially responsible for insulin resistance in liver. Because insulin binding and insulin stimulation of receptor kinase were normal in muscle of HFS-fed animals, it is concluded that the insulin resistance of glucose uptake into muscle is caused by a defect distal to the insulin receptor.

scholarly journals Internalization and Activation of the Rat Liver Insulin Receptor Kinase in vivo

1989 ◽  
Vol 264 (22) ◽  
pp. 12931-12940 ◽  
Author(s):  
M N Khan ◽  
G Baquiran ◽  
C Brule ◽  
J Burgess ◽  
B Foster ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Rat Liver ◽  
Receptor Kinase ◽  
Insulin Receptor Kinase
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