Biochemical and Biophysical Research Communications
Roles of mTOR and JNK in serine phosphorylation, translocation, and degradation of IRS-1☆
Section snippets
Materials and methods
Materials. The Lilly Research Laboratories (Indianapolis, IN) kindly provided porcine insulin. Anti-IRS-1 and anti-phospho-Ser307IRS-1 antibodies were purchased from Upstate Biotechnology (Lake Placid, NY). Anti-phospho-Ser636/639IRS-1, anti-phospho-Thr389p70S6K, and anti-phospho-Ser63c-Jun antibodies were purchased from Cell Signaling Technology (Beverly, MA). HRP-conjugated anti-immunoglobulin G secondary antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Rapamycin was
Roles of mTOR and JNK in phosphorylation of IRS-1 at Ser307 and Ser636/639 induced by insulin or anisomycin
To evaluate the roles of mTOR and JNK in Ser phosphorylation of IRS-1 induced by either insulin or anisomycin, we first examined the effects of the specific mTOR inhibitor, rapamycin [14], or JNK inhibitor, SP600125 [15], on phosphorylation of IRS-1 at Ser307 and Ser636/639 as well as phosphorylation of p70S6K at Thr389, which depends upon activation of mTOR pathway [16] and phosphorylation of c-Jun at Ser63, which is the direct target of JNK [15] (Fig. 1).
Insulin stimulation for 1 h induced
Discussion
In this study, we investigated the roles of mTOR and JNK in Ser phosphorylation, translocation, and degradation of IRS-1 in 3T3-L1 adipocytes stimulated either by insulin or anisomycin (Fig. 5). Despite the similar extent of phosphorylation of the same residues, Ser307 and Ser636/639, insulin and anisomycin were different in terms of the relationship of activation between mTOR and JNK, while both of them seem to cooperate in phosphorylating the serine residues. Insulin and anisomycin were also
Acknowledgments
This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan (to T.H.).
References (19)
- et al.
Insulin-stimulated GLUT4 translocation is mediated by a divergent intracellular signaling pathway
J. Biol. Chem.
(1995) - et al.
Activated phosphatidylinositol 3-kinase is sufficient to mediate actin rearrangement and GLUT4 translocation in 3T3-L1 adipocytes
J. Biol. Chem.
(1996) - et al.
Restraining PI3K: mTOR signalling goes back to the membrane
Trends Biochem. Sci.
(2005) - et al.
The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307
J. Biol. Chem.
(2000) - et al.
Mammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation
Biochem. Biophys. Res. Commun.
(2004) - et al.
Phosphorylation and Functional Inactivation of TSC2 by Erk: implications for tuberous sclerosis and cancer pathogenesis
Cell
(2005) - et al.
Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by serine 312 phosphorylation
J. Biol. Chem.
(2003) - et al.
Tumor necrosis factor α inhibits signaling from the insulin receptor
Proc. Natl. Acad. Sci. USA
(1994) - et al.
IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α and obesity-induced insulin resistance
Science
(1996)
Cited by (72)
Pregnane X receptor activation remodels glucose metabolism to promote NAFLD development in obese mice
2023, Molecular MetabolismAn insight into crosstalk among multiple signaling pathways contributing to epileptogenesis
2021, European Journal of PharmacologyCitation Excerpt :JNK1 and JNK2 are expressed universally, while expression of JNK3 is limited in the brain (Davis, 2000). Along with alteration of neuronal activity, JNK family members also control other biological activities and proteins like transcription factors, such as ATF2, Elk-1, stat3 (Jing and Anning, 2005; Miyazaki et al., 2008; Whitmarsh and Davis, 1996), and c-Myc (Noguchi et al., 1999), as well as members of the Bcl-2 family (Bcl-2, Bcl-xL, Bim, and BAD), IRS-1, Itch, and Tau, etc. through phosphorylation (Hiratani et al., 2005; Yamamoto et al., 1999; Yu et al., 2004). The Wnt pathway is vital for neural patterning and plasticity, apoptosis, cell polarity, and other developmental processess.
Cigarette smoking and nicotine exposure contributes for aberrant insulin signaling and cardiometabolic disorders
2021, European Journal of PharmacologyPolyphenol-rich extract of Zhenjiang aromatic vinegar ameliorates high glucose-induced insulin resistance by regulating JNK-IRS-1 and PI3K/Akt signaling pathways
2021, Food ChemistryCitation Excerpt :It has been reported that high glucose promotes the elevation of ROS level, which plays an important role in high glucose-induced IR (Evans, Goldfine, Maddux, & Grodsky, 2002). Several studies have demonstrated that IR in liver cells is accompanied by the phosphorylation of JNK and IRS-1 (Hiratani et al., 2005; Solinas, & Becattini, 2016). C-terminal-binding protein 2 (CtBP2) down-regulated palmitate-induced IR by inhibition of ROS accumulation and inactivation of JNK in HepG2 cell (Liu et al., 2017).
Long noncoding RNA MALAT1 regulates generation of reactive oxygen species and the insulin responses in male mice
2018, Biochemical PharmacologyActivation of the stress response kinase JNK (c-Jun N-terminal kinase) attenuates insulin action in retina through a p70S6K1-dependent mechanism
2017, Journal of Biological Chemistry
- ☆
Abbreviations: IRS, insulin receptor substrate; JNK, c-Jun N-terminal kinase; mTOR, mammalian target of rapamycin; PI 3-kinase, phosphatidylinositol 3-kinase; TSC, tuberous sclerosis complex; LDM, low-density microsomes; p70S6K, p70 S6 kinase.