scholarly journals β-Cell Receptor Tyrosine Kinases in Controlling Insulin Secretion and Exocytotic Machinery: c-Kit and Insulin Receptor

Endocrinology ◽  
2018 ◽  
Vol 159 (11) ◽  
pp. 3813-3821 ◽  
Author(s):  
Amanda Oakie ◽  
Rennian Wang
Keyword(s):  
Insulin Secretion ◽  
Insulin Receptor ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Cell Receptor ◽  
Β Cell

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 Effects of the Antitumor Drug OSI-906, a Dual Inhibitor of IGF-1 Receptor and Insulin Receptor, on the Glycemic Control, β-Cell Functions, and β-Cell Proliferation in Male Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (6) ◽  
pp. 2102-2111 ◽  
Author(s):  
Jun Shirakawa ◽  
Tomoko Okuyama ◽  
Eiko Yoshida ◽  
Mari Shimizu ◽  
Yuka Horigome ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glycemic Control ◽  
Insulin Receptor ◽  
Cell Mass ◽  
Male Mice ◽  
Β Cell ◽  
Dual Inhibitor ◽  
Cell Functions

The IGF-1 receptor has become a therapeutic target for the treatment of cancer. The efficacy of OSI-906 (linstinib), a dual inhibitor of IGF-1 receptor and insulin receptor, for solid cancers has been examined in clinical trials. The effects of OSI-906, however, on the blood glucose levels and pancreatic β-cell functions have not yet been reported. We investigated the impact of OSI-906 on glycemic control, insulin secretion, β-cell mass, and β-cell proliferation in male mice. Oral administration of OSI-906 worsened glucose tolerance in a dose-dependent manner in the wild-type mice. OSI-906 at a dose equivalent to the clinical daily dose (7.5 mg/kg) transiently evoked glucose intolerance and hyperinsulinemia. Insulin receptor substrate (IRS)-2-deficient mice and mice with diet-induced obesity, both models of peripheral insulin resistance, exhibited more severe glucose intolerance after OSI-906 administration than glucokinase-haploinsufficient mice, a model of impaired insulin secretion. Phloridzin improved the hyperglycemia induced by OSI-906 in mice. In vitro, OSI-906 showed no effect on insulin secretion from isolated islets. After daily administration of OSI-906 for a week to mice, the β-cell mass and β-cell proliferation rate were significantly increased. The insulin signals in the β-cells were apparently unaffected in those mice. Taken together, the results suggest that OSI-906 could exacerbate diabetes, especially in patients with insulin resistance. On the other hand, the results suggest that the β-cell mass may expand in response to chemotherapy with this drug.

scholarly journals Suppressors of T-cell Receptor Signaling Sts-1 and Sts-2 Bind to Cbl and Inhibit Endocytosis of Receptor Tyrosine Kinases

2004 ◽  
Vol 279 (31) ◽  
pp. 32786-32795 ◽  
Author(s):  
Katarzyna Kowanetz ◽  
Nicola Crosetto ◽  
Kaisa Haglund ◽  
Mirko H. H. Schmidt ◽  
Carl-Henrik Heldin ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Cell Receptor ◽  
Receptor Signaling ◽  
T Cell Receptor Signaling ◽  
Cell Receptor Signaling

Reduced β-cell mass and altered glucose sensing impair insulin-secretory function in βIRKO mice

2004 ◽  
Vol 286 (1) ◽  
pp. E41-E49 ◽  
Author(s):  
Kenichi Otani ◽  
Rohit N. Kulkarni ◽  
Aaron C. Baldwin ◽  
Jan Krutzfeldt ◽  
Kohjiro Ueki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Insulin Receptor ◽  
Cell Mass ◽  
Glucose Sensing ◽  
Β Cell ◽  
Isolated Perfused Pancreas ◽  
Altered Glucose ◽  
Glucose Tolerant ◽  
Insulin Mrna

Pancreatic β-cell-restricted knockout of the insulin receptor results in hyperglycemia due to impaired insulin secretion, suggesting that this cell is an important target of insulin action. The present studies were undertaken in β-cell insulin receptor knockout (βIRKO) mice to define the mechanisms underlying the defect in insulin secretion. On the basis of responses to intraperitoneal glucose, ∼7-mo-old βIRKO mice were either diabetic (25%) or normally glucose tolerant (75%). Total insulin content was profoundly reduced in pancreata of mutant mice compared with controls. Both groups also exhibited reduced β-cell mass and islet number. However, insulin mRNA and protein were similar in islets of diabetic and normoglycemic βIRKO mice compared with controls. Insulin secretion in response to insulin secretagogues from the isolated perfused pancreas was markedly reduced in the diabetic βIRKOs and to a lesser degree in the nondiabetic βIRKO group. Pancreatic islets of nondiabetic βIRKO animals also exhibited defects in glyceraldehyde- and KCl-stimulated insulin release that were milder than in the diabetic animals. Gene expression analysis of islets revealed a modest reduction of GLUT2 and glucokinase gene expression in both the nondiabetic and diabetic mutants. Taken together, these data indicate that loss of functional receptors for insulin in β-cells leads primarily to profound defects in postnatal β-cell growth. In addition, altered glucose sensing may also contribute to defective insulin secretion in mutant animals that develop diabetes.

scholarly journals α2-adrenergic signaling disrupts β cell BDNF-TrkB receptor tyrosine kinase signaling

2018 ◽  
Author(s):  
Michael A. Kalwat ◽  
Zhimin Huang ◽  
Derk D. Binns ◽  
Kathleen McGlynn ◽  
Melanie H. Cobb
Keyword(s):  
Insulin Secretion ◽  
Tyrosine Kinases ◽  
Careful Consideration ◽  
Mitogen Activated Protein Kinase ◽  
Published Data ◽  
High Dose ◽  
Kinase Signaling ◽  
Β Cells ◽  
Β Cell ◽  
Adrenergic Signaling

AbstractAdrenergic signaling is a well-known input into pancreatic islet function. Specifically, the insulin-secreting islet β cell expresses the Gi/o-linked α2-adrenergic receptor, which upon activation suppresses insulin secretion. The use of adrenergic agonist epinephrine at micromolar doses may have supraphysiological effects. We found that pretreating β cells with micromolar concentrations of epinephrine differentially inhibited activation of receptor tyrosine kinases. We chose TrkB as an example because of its relative sensitivity to the effects of epinephrine and due to its potential regulatory role in the β cell. Our characterization of brain-derived neurotrophic factor (BDNF)-TrkB signaling in MIN6 β cells showed that TrkB is activated by BDNF as expected, leading to canonical TrkB autophosphorylation and subsequent downstream signaling, as well as chronic effects on β cell growth. Micromolar, but not nanomolar, concentrations of epinephrine blocked BDNF-induced TrkB autophosphorylation and downstream mitogen-activated protein kinase pathway activation, suggesting an inhibitory phenomenon at the receptor level. We determined epinephrine-mediated inhibition of TrkB activation to be Gi/o-dependent using pertussis toxin, arguing against an off-target effect of high dose epinephrine. Published data suggested that inhibition of potassium channels or phosphoinositide-3-kinase signaling may abrogate the negative effects of epinephrine, however these did not rescue TrkB signaling in our experiments. Taken together, these results show that 1) TrkB kinase signaling occurs in β cells and 2) use of epinephrine in studies of insulin secretion requires careful consideration of concentration-dependent effects. BDNF-TrkB signaling in β cells may underlie pro-survival or growth signaling and warrants further study.

Suppressor of T-cell receptor signalling 1 and 2 differentially regulate endocytosis and signalling of receptor tyrosine kinases

FEBS Letters ◽  
2007 ◽  
Vol 581 (24) ◽  
pp. 4767-4772 ◽  
Author(s):  
Josipa Raguz ◽  
Sebastian Wagner ◽  
Ivan Dikic ◽  
Daniela Hoeller
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Cell Receptor ◽  
Receptor Signalling

The insulin receptor: structure, function, and signaling

1994 ◽  
Vol 266 (2) ◽  
pp. C319-C334 ◽  
Author(s):  
J. Lee ◽  
P. F. Pilch
Keyword(s):  
Insulin Receptor ◽  
Tyrosine Kinases ◽  
Intracellular Signaling ◽  
Metabolic Regulation ◽  
Receptor Tyrosine Kinases ◽  
Physiological Role ◽  
Biochemical Properties ◽  
Therapeutic Interventions ◽  
Intracellular Signaling Pathway ◽  
Effector Molecules

The insulin receptor is a member of the ligand-activated receptor and tyrosine kinase family of transmembrane signaling proteins that collectively are fundamentally important regulators of cell differentiation, growth, and metabolism. The insulin receptor has a number of unique physiological and biochemical properties that distinguish it from other members of this large well-studied receptor family. The main physiological role of the insulin receptor appears to be metabolic regulation, whereas all other receptor tyrosine kinases are engaged in regulating cell growth and/or differentiation. Receptor tyrosine kinases are allosterically regulated by their cognate ligands and function as dimers. In all cases but the insulin receptor (and 2 closely related receptors), these dimers are noncovalent, but insulin receptors are covalently maintained as functional dimers by disulfide bonds. The initial response to the ligand is receptor autophosphorylation for all receptor tyrosine kinases. In most cases, this results in receptor association of effector molecules that have unique recognition domains for phosphotyrosine residues and whose binding to these results in a biological response. For the insulin receptor, this does not occur; rather, it phosphorylates a large substrate protein that, in turn, engages effector molecules. Possible reasons for these differences are discussed in this review. The chemistry of insulin is very well characterized because of possible therapeutic interventions in diabetes using insulin derivatives. This has allowed the synthesis of many insulin derivatives, and we review our recent exploitation of one such derivative to understand the biochemistry of the interaction of this ligand with the receptor and to dissect the complicated steps of ligand-induced insulin receptor autophosphorylation. We note possible future directions in the study of the insulin receptor and its intracellular signaling pathway(s).

scholarly journals Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic β-cells

2009 ◽  
Vol 44 (3) ◽  
pp. 171-178 ◽  
Author(s):  
James E P Brown ◽  
David J Onyango ◽  
Manjunath Ramanjaneya ◽  
Alex C Conner ◽  
Snehal T Patel ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Receptor ◽  
Mrna Expression ◽  
Fold Increase ◽  
Receptor Activation ◽  
Nuclear Factor ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Nicotinamide Phosphoribosyltransferase

The role of the adipocyte-derived factor visfatin in metabolism remains controversial, although some pancreatic β-cell-specific effects have been reported. This study investigated the effects of visfatin upon insulin secretion, insulin receptor activation and mRNA expression of key diabetes-related genes in clonal mouse pancreatic β-cells. β-TC6 cells were cultured in RPMI 1640 and were subsequently treated with recombinant visfatin. One-hour static insulin secretion was measured by ELISA. Phospho-specific ELISA and western blotting were used to detect insulin receptor activation. Real-time SYBR Green PCR array technology was used to measure the expression of 84 diabetes-related genes in both treatment and control cells. Incubation with visfatin caused significant changes in the mRNA expression of several key diabetes-related genes, including marked up-regulation of insulin (9-fold increase), hepatocyte nuclear factor (HNF)1β (32-fold increase), HNF4α (16-fold increase) and nuclear factor κB (40-fold increase). Significant down-regulation was seen in angiotensin-converting enzyme (−3.73-fold) and UCP2 (−1.3-fold). Visfatin also caused a significant 46% increase in insulin secretion compared to control (P<0.003) at low glucose, and this increase was blocked by co-incubation with the specific nicotinamide phosphoribosyltransferase inhibitor FK866. Both visfatin and nicotinamide mononucleotide induced activation of both insulin receptor and extracellular signal-regulated kinase (ERK)1/2, with visfatin-induced insulin receptor/ERK1/2 activation being inhibited by FK866. We conclude that visfatin can significantly regulate insulin secretion, insulin receptor phosphorylation and intracellular signalling and the expression of a number of β-cell function-associated genes in mouse β-cells.

Targeting of host cell receptor tyrosine kinases by intracellular pathogens

2019 ◽  
Vol 12 (599) ◽  
pp. eaau9894 ◽  
Author(s):  
Gholamreza Haqshenas ◽  
Christian Doerig
Keyword(s):  
Host Cell ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Cell Receptor ◽  
Host Cells ◽  
Target Cells ◽  
Intracellular Pathogens ◽  
Host Cell Receptor ◽  
Host Signaling ◽  
Mediate Cell

Intracellular pathogens use complex and tightly regulated processes to enter host cells. Upon initial interactions with signaling proteins at the surface of target cells, intracellular microbes activate and co-opt specific host signaling pathways that mediate cell surface–cytosol communications to facilitate pathogen internalization. Here, we discuss the roles of host receptor tyrosine kinases (RTKs) in the establishment of productive infections by major intracellular pathogens. We evaluate the gaps in the current understanding of this process and propose a comprehensive approach for assessing the role of host cell signaling in the biology of intracellular microorganisms and viruses. We also discuss RTK-targeting strategies for the treatment of various infections.

scholarly journals Intrasteric Inhibition of ATP Binding Is Not Required To Prevent Unregulated Autophosphorylation or Signaling by the Insulin Receptor

2001 ◽  
Vol 21 (13) ◽  
pp. 4197-4207 ◽  
Author(s):  
Mark Frankel ◽  
Ararat J. Ablooglu ◽  
Joseph W. Leone ◽  
Elena Rusinova ◽  
J. B. Alexander Ross ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Conformational Changes ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Kinase Domain ◽  
Atp Binding ◽  
Activation Loop ◽  
Wild Type ◽  
Solution Studies ◽  
Activated State

ABSTRACT Receptor tyrosine kinases may use intrasteric inhibition to suppress autophosphorylation prior to growth factor stimulation. To test this hypothesis we made an Asp1161Ala mutant in the activation loop that relieved intrasteric inhibition of the unphosphorylated insulin receptor (IR) and its recombinant cytoplasmic kinase domain (IRKD) without affecting the activated state. Solution studies with the unphosphorylated mutant IRKD demonstrated conformational changes and greater catalytic efficiency from a 10-fold increase ink cat and a 15-fold-lowerK m ATP althoughK m peptide was unchanged. Kinetic parameters of the autophosphorylated mutant and wild-type kinase domains were virtually identical. The Asp1161Ala mutation increased the rate of in vitro autophosphorylation of the IRKD or IR at low ATP concentrations and in the absence of insulin. However, saturation with ATP (for the IRKD) or the presence of insulin (for the IR) yielded equivalent rates of autophosphorylation for mutant versus wild-type kinases. Despite a biochemically more active kinase domain, the mutant IR expressed in C2C12 myoblasts was not constitutively autophosphorylated. However, it displayed a 2.5-fold-lower 50% effective concentration for insulin stimulation of autophosphorylation and was dephosphorylated more slowly following withdrawal of insulin than wild-type IR. In tests of the regulation of the unphosphorylated basal state, these results demonstrate that neither intrasteric inhibition against ATP binding nor suppression of kinase activity is required to prevent premature autophosphorylation of the IR. Finally, the lower rate of dephosphorylation suggests invariant residues of the activation loop such as Asp1161 may function at multiple junctures in cellular regulation of receptor tyrosine kinases.

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