Binding of SH2 containing proteins to the insulin receptor: A new way for modulating insulin signalling

1998 ◽  
pp. 73-78 ◽  
Author(s):  
Feng Liu ◽  
Richard A. Roth
Keyword(s):  
Insulin Receptor ◽  
Insulin Signalling

scholarly journals Tyrosine kinase activity of liver insulin receptor is inhibited in rats at term gestation

1989 ◽  
Vol 263 (1) ◽  
pp. 267-272 ◽  
Author(s):  
C Martínez ◽  
P Ruiz ◽  
A Andrés ◽  
J Satrústegui ◽  
J M Carrascosa
Keyword(s):  
Insulin Receptor ◽  
Kinase Activity ◽  
Insulin Signalling ◽  
Insulin Receptors ◽  
Insulin Binding ◽  
Late Gestation ◽  
Receptor Kinase ◽  
Pregnant Rats ◽  
Insulin Resistant ◽  
32P Incorporation

Late gestation is associated with insulin resistance in rats and humans. It has been reported that rats at term gestation show active hepatic gluconeogenesis and glycogenolysis, and diminished lipogenesis, despite normal or mildly elevated plasma insulin concentrations, indicating a state of resistance to the hormone action. Since autophosphorylation of the insulin receptor has been reported to play a key role in the hormone signal transduction, we have partially purified plasma-membrane liver insulin receptors from virgin and 22-day-pregnant rats and studied their binding and kinase activities. (1) Insulin binding to partially purified receptors does not appear to be influenced by gestation, as indicated by the observed KD and Bmax. values. (2) The rate of autophosphorylation and the maximal 32P incorporation into the receptor beta-subunit from pregnant rats at saturating concentrations of insulin are markedly decreased with respect to the corresponding values for virgin rats. (3) The diminished autophosphorylation rate was due to a decreased responsiveness of the kinase activity to the action of insulin. (4) Phosphorylation of the exogenous substrates casein and poly(Glu80Tyr20) by insulin-receptor kinase was also less when receptors from pregnant rats were used. These results show the existence of an impairment at the receptor kinase level of the insulin signalling mechanism that might be related to the insulin-resistant state characteristic of term gestation in rats.

scholarly journals Insulin signalling: putting the G- in protein-protein interactions

2004 ◽  
Vol 380 (1) ◽  
pp. e11-e12 ◽  
Author(s):  
Craig C. MALBON
Keyword(s):  
Insulin Receptor ◽  
Cross Talk ◽  
Protein Interactions ◽  
Tyrosine Kinases ◽  
Cell Biology ◽  
Receptor Tyrosine Kinases ◽  
Insulin Signalling ◽  
Cell Signalling ◽  
Protein Protein Interactions ◽  
Proximal Point

Cell signalling via receptor tyrosine kinases, such as the insulin receptor, and via heterotrimeric G-proteins, such as Gαi, Gαs and Gαq family members, constitute two of most avidly studied paradigms in cell biology. That elements of these two populous signalling pathways must cross-talk to achieve proper signalling in the regulation of cell proliferation, differentiation and metabolism has been anticipated, but the evolution of our thinking and the analysis of such cross-talk have lagged behind the ever-expanding troupe of players and the recognition of multivalency as the rule, rather than the exception, in signalling biology. New insights have been provided by Kreuzer et al. in this issue of the Biochemical Journal, in which insulin is shown to provoke recruitment of Gαi-proteins to insulin-receptor-based complexes that can regulate the gain of insulin-receptor-catalysed autophosphorylation, a proximal point in the insulin-sensitive cascade of signalling. Understanding the convergence and cross-talk of signals from the receptor tyrosine kinases and G-protein-coupled receptor pathways in physical, spatial and temporal contexts will remain a major challenge of cell biology.

scholarly journals Interaction of protein tyrosine phosphatase (PTP) 1B with its substrates is influenced by two distinct binding domains

2002 ◽  
Vol 364 (2) ◽  
pp. 377-383 ◽  
Author(s):  
Shrikrishna DADKE ◽  
Jonathan CHERNOFF
Keyword(s):  
Insulin Receptor ◽  
Protein Tyrosine Phosphatase ◽  
Insulin Signalling ◽  
Tyrosine Phosphatase ◽  
Rich Region ◽  
Protein Tyrosine ◽  
Binding Domains ◽  
C Terminus ◽  
Ptp 1B ◽  
Proline Rich Region

We have shown previously that protein tyrosine phosphatase (PTP) 1B interacts with insulin receptor and negatively regulates insulin signalling by an N-terminal binding domain [Dadke, Kusari and Chernoff (2000) J. Biol. Chem. 275, 23642–23647] and it also negatively regulates integrin signalling through a proline-rich region present in the C-terminus [Liu, Hill and Chernoff (1996) J. Biol. Chem. 271, 31290–31295; Liu, Sells and Chernoff (1998) Curr. Biol. 8, 173–176]. Here we show that PTP1B mutants that are defective in Src homology 3 domain binding fully retain the ability to inhibit insulin signalling, whereas mutants defective in insulin-receptor binding fully retain the ability to inhibit integrin signalling. In contrast, both the C-terminal proline-rich region and the tandem tyrosine residues present in the N-terminal region are required for the activation of Src family kinases. These data show that PTP1B can independently regulate insulin and integrin signals, and that Src might represent a convergence point for regulating signal transduction by this phosphatase.

The R3 receptor-like protein tyrosine phosphatase subfamily inhibits insulin signalling by dephosphorylating the insulin receptor at specific sites

2015 ◽  
Vol 158 (3) ◽  
pp. 235-243 ◽  
Author(s):  
Takafumi Shintani ◽  
Satoru Higashi ◽  
Yasushi Takeuchi ◽  
Eugenio Gaudio ◽  
Francesco Trapasso ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Protein Tyrosine Phosphatase ◽  
Insulin Signalling ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine

scholarly journals Momordica charantia (bitter melon) reduces plasma apolipoprotein B-100 and increases hepatic insulin receptor substrate and phosphoinositide-3 kinase interactions

2008 ◽  
Vol 100 (4) ◽  
pp. 751-759 ◽  
Author(s):  
Pratibha V. Nerurkar ◽  
Yun Kyung Lee ◽  
Megan Motosue ◽  
Khosrow Adeli ◽  
Vivek R. Nerurkar
Keyword(s):  
Insulin Receptor ◽  
Animal Studies ◽  
Molecular Mechanisms ◽  
Insulin Signalling ◽  
Plasma Lipid ◽  
Momordica Charantia ◽  
Bitter Melon ◽  
Human Hepatoma Cells ◽  
Signalling Molecules ◽  
Phosphoinositide 3 Kinase

Aqueous extracts or juice from unripened fruit of Momordica charantia (bitter melon) has traditionally been used in the treatment of diabetes and its complications. Insulin resistance is characterized by significant down-regulation of hepatic insulin signalling as documented by attenuated phosphorylation of insulin receptor (IR), IR substrates 1 and 2, phosphoinositide-3 kinase, protein kinase B, and over-expression of phosphotyrosine phosphatase 1B. We recently demonstrated that bitter melon juice (BMJ) is a potent inhibitor of apoB secretion and TAG synthesis and secretion in human hepatoma cells, HepG2, that may be involved in plasma lipid- and VLDL-lowering effects observed in animal studies. The aim of this study was to evaluate the effects of BMJ on plasma apoB levels and hepatic insulin signalling cascade in mice fed high-fat diet (HFD). Female C57BL/6 mice (4–6 weeks old) were randomized into three groups receiving regular rodent chow, HFD and HFD+BMJ. The data indicate that BMJ not only improves glucose and insulin tolerance but also lowers plasma apoB-100 and apoB-48 in HFD-fed mice as well as modulates the phosphorylation status of IR and its downstream signalling molecules. Investigating the biochemical and molecular mechanisms involved in amelioration of diabetic dyslipidaemia by BMJ may lead to identification of new molecular targets for dietary/alternative therapies.

scholarly journals A novel regulation of IRS1 (insulin receptor substrate-1) expression following short term insulin administration

2005 ◽  
Vol 392 (2) ◽  
pp. 345-352 ◽  
Author(s):  
Antonio J. Ruiz-Alcaraz ◽  
Hui-Kang Liu ◽  
Daniel J. Cuthbertson ◽  
Edward J. Mcmanus ◽  
Simeen Akhtar ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Insulin Signalling ◽  
Insulin Injection ◽  
Underlying Mechanism ◽  
Type Ii Diabetes Mellitus ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Insulin Receptor Tyrosine Kinase ◽  
Cell Culture Systems ◽  
Or Gene

Reduced insulin-mediated glucose transport in skeletal muscle is a hallmark of the pathophysiology of T2DM (Type II diabetes mellitus). Impaired intracellular insulin signalling is implicated as a key underlying mechanism. Attention has focused on early signalling events such as defective tyrosine phosphorylation of IRS1 (insulin receptor substrate-1), a major target for the insulin receptor tyrosine kinase. This is required for normal induction of signalling pathways key to many of the metabolic actions of insulin. Conversely, increased serine/threonine phosphorylation of IRS1 following prolonged insulin exposure (or in obesity) reduces signalling capacity, partly by stimulating IRS1 degradation. We now show that IRS1 levels in human muscle are actually increased 3-fold following 1 h of hyperinsulinaemic euglycaemia. Similarly, transient induction of IRS1 (3-fold) in the liver or muscle of rodents occurs following feeding or insulin injection respectively. The induction by insulin is also observed in cell culture systems, although to a lesser degree, and is not due to reduced proteasomal targeting, increased protein synthesis or gene transcription. Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function. Impairment of this process would reduce IRS1 signalling capacity, thereby contributing to the development of hyperinsulinaemia/insulin resistance prior to the appearance of T2DM.

scholarly journals Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex

2014 ◽  
Vol 70 (10) ◽  
pp. 2765-2774 ◽  
Author(s):  
Lenka Žáková ◽  
Emília Kletvíková ◽  
Martin Lepšík ◽  
Michaela Collinsová ◽  
Christopher J. Watson ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Insulin Signalling ◽  
Active Form ◽  
Insulin Analogues ◽  
Receptor Complex ◽  
Structural Insight ◽  
Natural Amino Acids ◽  
Receptor Interface ◽  
Insight Into

The structural characterization of the insulin–insulin receptor (IR) interaction still lacks the conformation of the crucial B21–B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]-insulin and [GlyB26]-insulin attain a B26-turn-like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26-turn-like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B-chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms.

scholarly journals Genetic engineering in mice: impact on insulin signalling and action1

1998 ◽  
Vol 335 (2) ◽  
pp. 193-204 ◽  
Author(s):  
Betty LAMOTHE ◽  
Anne BAUDRY ◽  
Pierrette DESBOIS ◽  
Lucianne LAMOTTE ◽  
Danielle BUCCHINI ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Cell Lines ◽  
Insulin Signalling ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Type I ◽  
Signalling Molecules ◽  
Severe Diabetes ◽  
Genes Encoding ◽  
Mitogenic Signalling

The expression of a number of genes encoding key players in insulin signalling and action, including insulin, insulin receptor (IR), downstream signalling molecules such as insulin receptor substrate-1 (IRS-1) and IRS-2, glucose transporters (GLUT4, GLUT2) and important metabolic enzymes such as glucokinase, has now been altered in transgenic or knockout mice. Such mice presented with phenotypes ranging from mild defects, revealing complementarity between key molecules or pathways, to severe diabetes with ketoacidosis and early postnatal death. Insulin action could also be improved by overproduction of proteins acting at regulatory steps. The development of diabetes by combining mutations, which alone do not lead to major metabolic alterations, validated the ‘diabetogenes ’ concept of non-insulin-dependent diabetes mellitus. Genes encoding insulin-like growth factors (IGF-I and IGF-II) and their type I receptor (IGF-IR) have also been disrupted. It appears that although IR and IGF-IR are both capable of metabolic and mitogenic signalling, they are not fully redundant. However, IR could replace IGF-IR if efficiently activated by IGF-II. Studies with cell lines lacking IR or IGF-IR lend support to such conclusions. Concerning the issues of specificity and redundancy, studies with cell lines derived from IRS-1-deficient mice showed that IRS-1 and IRS-2 are also not completely interchangeable.

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