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Phosphorylation of IRS1 at serine 307 in response to insulin in human adipocytes is not likely to be catalyzed by p70 ribosomal S6 kinase.
PLoS One. 2013; 8(4):e59725.Plos

Abstract

The insulin receptor substrate-1 (IRS1) is phosphorylated on serine 307 (human sequence, corresponding to murine serine 302) in response to insulin as part of a feedback loop that controls IRS1 phosphorylation on tyrosine residues by the insulin receptor. This in turn directly affects downstream signaling and is in human adipocytes implicated in the pathogenesis of insulin resistance and type 2 diabetes. The phosphorylation is inhibited by rapamycin, a specific inhibitor of mammalian target of rapamycin (mTOR) in complex with raptor (mTORC1). The mTORC1-downstream p70 ribosomal protein S6 kinase (S6K1), which is activated by insulin, can phosphorylate IRS1 at serine 307 in vitro and is considered the physiological protein kinase. Because the IRS1 serine 307-kinase catalyzes a critical step in the control of insulin signaling and constitutes a potential target for treatment of insulin resistance, it is important to know whether S6K1 is the physiological serine 307-kinase or not. We report that, by several criteria, S6K1 does not phosphorylate IRS1 at serine 307 in response to insulin in intact human primary adipocytes: (i) The time-courses for phosphorylation of S6K1 and its phosphorylation of S6 are not compatible with the phosphorylation of IRS1 at serine 307; (ii) A dominant-negative construct of S6K1 inhibits the phosphorylation of S6, without effect on the phosphorylation of IRS1 at serine 307; (iii) The specific inhibitor of S6K1 PF-4708671 inhibits the phosphorylation of S6, without effect on phosphorylation of IRS1 at serine 307. mTOR-immunoprecipitates from insulin-stimulated adipocytes contains an unidentified protein kinase specific for phosphorylation of IRS1 at serine 307, but it is not mTOR or S6K1.

Authors+Show Affiliations

Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23565163

Citation

Rajan, Meenu Rohini, et al. "Phosphorylation of IRS1 at Serine 307 in Response to Insulin in Human Adipocytes Is Not Likely to Be Catalyzed By P70 Ribosomal S6 Kinase." PloS One, vol. 8, no. 4, 2013, pp. e59725.
Rajan MR, Fagerholm S, Jönsson C, et al. Phosphorylation of IRS1 at serine 307 in response to insulin in human adipocytes is not likely to be catalyzed by p70 ribosomal S6 kinase. PLoS ONE. 2013;8(4):e59725.
Rajan, M. R., Fagerholm, S., Jönsson, C., Kjølhede, P., Turkina, M. V., & Strålfors, P. (2013). Phosphorylation of IRS1 at serine 307 in response to insulin in human adipocytes is not likely to be catalyzed by p70 ribosomal S6 kinase. PloS One, 8(4), e59725. https://doi.org/10.1371/journal.pone.0059725
Rajan MR, et al. Phosphorylation of IRS1 at Serine 307 in Response to Insulin in Human Adipocytes Is Not Likely to Be Catalyzed By P70 Ribosomal S6 Kinase. PLoS ONE. 2013;8(4):e59725. PubMed PMID: 23565163.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phosphorylation of IRS1 at serine 307 in response to insulin in human adipocytes is not likely to be catalyzed by p70 ribosomal S6 kinase. AU - Rajan,Meenu Rohini, AU - Fagerholm,Siri, AU - Jönsson,Cecilia, AU - Kjølhede,Preben, AU - Turkina,Maria V, AU - Strålfors,Peter, Y1 - 2013/04/02/ PY - 2012/11/19/received PY - 2013/02/17/accepted PY - 2013/4/9/entrez PY - 2013/4/9/pubmed PY - 2013/10/31/medline SP - e59725 EP - e59725 JF - PloS one JO - PLoS ONE VL - 8 IS - 4 N2 - The insulin receptor substrate-1 (IRS1) is phosphorylated on serine 307 (human sequence, corresponding to murine serine 302) in response to insulin as part of a feedback loop that controls IRS1 phosphorylation on tyrosine residues by the insulin receptor. This in turn directly affects downstream signaling and is in human adipocytes implicated in the pathogenesis of insulin resistance and type 2 diabetes. The phosphorylation is inhibited by rapamycin, a specific inhibitor of mammalian target of rapamycin (mTOR) in complex with raptor (mTORC1). The mTORC1-downstream p70 ribosomal protein S6 kinase (S6K1), which is activated by insulin, can phosphorylate IRS1 at serine 307 in vitro and is considered the physiological protein kinase. Because the IRS1 serine 307-kinase catalyzes a critical step in the control of insulin signaling and constitutes a potential target for treatment of insulin resistance, it is important to know whether S6K1 is the physiological serine 307-kinase or not. We report that, by several criteria, S6K1 does not phosphorylate IRS1 at serine 307 in response to insulin in intact human primary adipocytes: (i) The time-courses for phosphorylation of S6K1 and its phosphorylation of S6 are not compatible with the phosphorylation of IRS1 at serine 307; (ii) A dominant-negative construct of S6K1 inhibits the phosphorylation of S6, without effect on the phosphorylation of IRS1 at serine 307; (iii) The specific inhibitor of S6K1 PF-4708671 inhibits the phosphorylation of S6, without effect on phosphorylation of IRS1 at serine 307. mTOR-immunoprecipitates from insulin-stimulated adipocytes contains an unidentified protein kinase specific for phosphorylation of IRS1 at serine 307, but it is not mTOR or S6K1. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/23565163/Phosphorylation_of_IRS1_at_serine_307_in_response_to_insulin_in_human_adipocytes_is_not_likely_to_be_catalyzed_by_p70_ribosomal_S6_kinase_ L2 - http://dx.plos.org/10.1371/journal.pone.0059725 DB - PRIME DP - Unbound Medicine ER -