scholarly journals Resistin Promotes Cardiac Hypertrophy via the AMP-activated Protein Kinase/Mammalian Target of Rapamycin (AMPK/mTOR) and c-Jun N-terminal Kinase/Insulin Receptor Substrate 1 (JNK/IRS1) Pathways

2011 ◽  
Vol 286 (21) ◽  
pp. 18465-18473 ◽  
Author(s):  
Soojeong Kang ◽  
Elie R. Chemaly ◽  
Roger J. Hajjar ◽  
Djamel Lebeche
Keyword(s):  
Protein Kinase ◽  
Cardiac Hypertrophy ◽  
Insulin Receptor ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Amp Activated Protein Kinase

scholarly journals Heparin-Binding EGF-Like Growth Factor (HB-EGF) Mediates 5-HT-Induced Insulin Resistance Through Activation of EGF Receptor-ERK1/2-mTOR Pathway

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 56-68 ◽  
Author(s):  
Qinkai Li ◽  
Toshio Hosaka ◽  
Yosuke Shikama ◽  
Yukiko Bando ◽  
Chisato Kosugi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Factor ◽  
Insulin Receptor ◽  
Egf Receptor ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Insulin Receptor Substrate ◽  
Heparin Binding ◽  
Insulin Receptor Substrate 1 ◽  
Endothelin 1

Although an inverse correlation between insulin sensitivity and the level of Gq/11-coupled receptor agonists, such as endothelin-1, thrombin, and 5-hydroxytryptamine (5-HT), has been reported, its precise mechanism remains unclear. In this report, we provide evidence that 5-HT induced production of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and caused insulin resistance in 3T3-L1 adipocytes, primary adipocytes, and C2C12 myotubes. In 3T3-L1 adipocytes, 5-HT stimulated HB-EGF production by promoting metalloproteinase-dependent shedding of transmembrane protein pro-HB-EGF. HB-EGF then bound and tyrosine-phosphorylated EGF receptors, which activated the mammalian target of rapamycin pathway through ERK1/2 phosphorylation. Mammalian target of rapamycin activation caused serine phosphorylation of insulin receptor substrate-1, which attenuated insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 and glucose uptake. Pharmacological inhibition of either Gq/11-coupled receptors or metalloproteinases, as well as either inhibition or knockdown of HB-EGF or Gαq/11, restored insulin signal transduction impaired by 5-HT. Inhibition of metalloproteinase activity also abolished HB-EGF production and subsequent EGF receptor activation by other Gq/11-coupled receptor agonists known to cause insulin resistance, such as endothelin-1 and thrombin. These results suggest that transactivation of the EGF receptor through HB-EGF processing plays a pivotal role in 5-HT-induced insulin resistance.

Mammalian Target of Rapamycin Is Activated in Association with Myometrial Proliferation during Pregnancy

Endocrinology ◽  
2009 ◽  
Vol 150 (10) ◽  
pp. 4672-4680 ◽  
Author(s):  
Shabana Jaffer ◽  
Oksana Shynlova ◽  
Stephen Lye
Keyword(s):  
Insulin Receptor ◽  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
Insulin Receptor Substrate ◽  
Mtor Signaling Pathway ◽  
Insulin Receptor Substrate 1 ◽  
Ovx Rats

Abstract The adaptive growth of the uterus during gestation involves gradual changes in cellular phenotypes from the early proliferative to the intermediate synthetic phase of cellular hypertrophy, ending in the final contractile/labour phenotype. The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth and proliferation in many tissues. We hypothesized that mTOR was a mediator of hormone-initiated myometrial hyperplasia during gestation. The protein expression and phosphorylation levels of mTOR, its upstream regulators [insulin receptor substrate-1, phosphoinositide-3-kinase (PI3K), Akt], and downstream effectors [S6-kinase-1 (S6K1) and eI4FE-binding protein 1 (4EBP1)] were analyzed throughout normal pregnancy in rats. In addition, we used an ovariectomized (OVX) rat model to analyze the modulation of the mTOR pathway and proliferative activity of the uterine myocytes by estradiol alone and in combination with the mTOR-specific inhibitor rapamycin. Our results demonstrate that insulin receptor substrate-1 protein levels and the phosphorylated (activated) forms of PI3K, mTOR, and S6K1 were significantly up-regulated in the rat myometrium during the proliferative phase of pregnancy. Treatment of the OVX rats with estradiol caused a transient increase in IGF-I followed by an up-regulation of the PI3K/mTOR pathway, which became apparent by a cascade of phosphorylation reactions (P-P85, P-Akt, P-mTOR, P-S6K1, and P-4EBP1). Rapamycin blocked activation of P-mTOR, P-S6K1, and P-4EBP1 proteins and significantly reduced the number of proliferating cells in the myometrium of OVX rats. Our in vivo data demonstrate that estradiol was able to activate the PI3K/mTOR signaling pathway in uterine myocytes and suggest that this activation is responsible for the induction of myometrial hyperplasia during early gestation.

scholarly journals Mammalian Target of Rapamycin Pathway Regulates Insulin Signaling via Subcellular Redistribution of Insulin Receptor Substrate 1 and Integrates Nutritional Signals and Metabolic Signals of Insulin

2001 ◽  
Vol 21 (15) ◽  
pp. 5050-5062 ◽  
Author(s):  
Atsuko Takano ◽  
Isao Usui ◽  
Tetsuro Haruta ◽  
Junko Kawahara ◽  
Tatsuhito Uno ◽  
...  
Keyword(s):  
Amino Acid ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Mammalian Target Of Rapamycin ◽  
Proteasomal Degradation ◽  
Target Of Rapamycin ◽  
Insulin Receptor Substrate ◽  
Amino Acid Deprivation ◽  
Insulin Receptor Substrate 1 ◽  
Amino Acid Availability

ABSTRACT A pathway sensitive to rapamycin, a selective inhibitor of mammalian target of rapamycin (mTOR), down-regulates effects of insulin such as activation of Akt (protein kinase B) via proteasomal degradation of insulin receptor substrate 1 (IRS-1). We report here that the pathway also plays an important role in insulin-induced subcellular redistribution of IRS-1 from the low-density microsomes (LDM) to the cytosol. After prolonged insulin stimulation, inhibition of the redistribution of IRS-1 by rapamycin resulted in increased levels of IRS-1 and the associated phosphatidylinositol (PI) 3-kinase in both the LDM and cytosol, whereas the proteasome inhibitor lactacystin increased the levels only in the cytosol. Since rapamycin but not lactacystin enhances insulin-stimulated 2-deoxyglucose (2-DOG) uptake, IRS-1-associated PI 3-kinase localized at the LDM was suggested to be important in the regulation of glucose transport. The amino acid deprivation attenuated and the amino acid excess enhanced insulin-induced Ser/Thr phosphorylation and subcellular redistribution and degradation of IRS-1 in parallel with the effects on phosphorylation of p70 S6 kinase and 4E-BP1. Accordingly, the amino acid deprivation increased and the amino acid excess decreased insulin-stimulated activation of Akt and 2-DOG uptake. Furthermore, 2-DOG uptake was affected by amino acid availability even when the degradation of IRS-1 was inhibited by lactacystin. We propose that subcellular redistribution of IRS-1, regulated by the mTOR-dependent pathway, facilitates proteasomal degradation of IRS-1, thereby down-regulating Akt, and that the pathway also negatively regulates insulin-stimulated glucose transport, probably through the redistribution of IRS-1. This work identifies a novel function of mTOR that integrates nutritional signals and metabolic signals of insulin.

scholarly journals Regulation of insulin receptor substrate-1 by mTORC2 (mammalian target of rapamycin complex 2)

2013 ◽  
Vol 41 (4) ◽  
pp. 896-901 ◽  
Author(s):  
Michael A. DeStefano ◽  
Estela Jacinto
Keyword(s):  
Growth Factors ◽  
Insulin Receptor ◽  
Insulin Signalling ◽  
Mammalian Target Of Rapamycin ◽  
Serine Phosphorylation ◽  
Target Of Rapamycin ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Cullin 7 ◽  
Mtor Complex 1

mTOR (mammalian target of rapamycin) responds to the presence of nutrients, energy and growth factors to link cellular metabolism, growth and proliferation. The rapamycin-sensitive mTORC (mTOR complex) 1 activates the translational regulator S6K (S6 kinase), leading to increased protein synthesis in the presence of nutrients. On the other hand, the rapamycin-insensitive mTORC2 responds to the presence of growth factors such as insulin by phosphorylating Akt to promote its maturation and allosteric activation. We recently found that mTORC2 can also regulate insulin signalling at the level of IRS-1 (insulin receptor substrate-1). Whereas mTORC1 promotes IRS-1 serine phosphorylation that is linked to IRS-1 down-regulation, we uncovered that mTORC2 mediates its degradation. In mTORC2-disrupted cells, inactive IRS-1 accumulated despite undergoing phosphorylation at the mTORC1-mediated serine sites. Defective IRS-1 degradation was due to attenuated expression of the CUL7 (Cullin 7) ubiquitin ligase substrate-targeting sub-unit Fbw8. mTORC2 and Fbw8 co-localize at the membrane where mTORC2 phosphorylates Ser86 to stabilize Fbw8 and promotes its cytosolic localization upon insulin stimulation. Under conditions of chronic insulin exposure, inactive serine-phosphorylated IRS-1 and Fbw8 co-localize to the cytosol where the former becomes ubiquitylated via CUL7/Fbw8. Thus mTORC2 negatively feeds back to IRS-1 via control of Fbw8 stability and localization. Our findings reveal that, in addition to persistent mTORC1 signalling, increased mTORC2 signals can promote insulin resistance due to mTORC2-mediated degradation of IRS-1.

scholarly journals Shp2 Is Required for Protein Kinase C-dependent Phosphorylation of Serine 307 in Insulin Receptor Substrate-1

2005 ◽  
Vol 280 (38) ◽  
pp. 32693-32699 ◽  
Author(s):  
Karsten Müssig ◽  
Harald Staiger ◽  
Hendrik Fiedler ◽  
Klaus Moeschel ◽  
Alexander Beck ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Kinase C
Sign in / Sign up

Export Citation Format

Share Document