Phosphatidylcholine Transfer Protein Interacts with Thioesterase Superfamily Member 2 to Attenuate Insulin Signaling

Overview

Journal Sci Signal

Specialties Cell Biology
Physiology
Science

Date 2013 Aug 1

PMID 23901139

Citations 18

Authors

Baran A Ersoy

Akansha Tarun

Katharine DAquino

Nancy J Hancer

Chinweike Ukomadu

Morris F White

Thomas Michel

Brendan D Manning

David E Cohen

Affiliations

Soon will be listed here.

Abstract

Phosphatidylcholine transfer protein (PC-TP) is a phospholipid-binding protein that is enriched in liver and that interacts with thioesterase superfamily member 2 (THEM2). Mice lacking either protein exhibit improved hepatic glucose homeostasis and are resistant to diet-induced diabetes. Insulin receptor substrate 2 (IRS2) and mammalian target of rapamycin complex 1 (mTORC1) are key effectors of insulin signaling, which is attenuated in diabetes. We found that PC-TP inhibited IRS2, as evidenced by insulin-independent IRS2 activation after knockdown, genetic ablation, or chemical inhibition of PC-TP. In addition, IRS2 was activated after knockdown of THEM2, providing support for a role for the interaction of PC-TP with THEM2 in suppressing insulin signaling. Additionally, we showed that PC-TP bound to tuberous sclerosis complex 2 (TSC2) and stabilized the components of the TSC1-TSC2 complex, which functions to inhibit mTORC1. Preventing phosphatidylcholine from binding to PC-TP disrupted interactions of PC-TP with THEM2 and TSC2, and disruption of the PC-TP-THEM2 complex was associated with increased activation of both IRS2 and mTORC1. In livers of mice with genetic ablation of PC-TP or that had been treated with a PC-TP inhibitor, steady-state amounts of IRS2 were increased, whereas those of TSC2 were decreased. These findings reveal a phospholipid-dependent mechanism that suppresses insulin signaling downstream of its receptor.

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References

Kang H, Wei J, Cohen D . PC-TP/StARD2: Of membranes and metabolism. Trends Endocrinol Metab. 2010; 21(7):449-56. PMC: 2897958. DOI: 10.1016/j.tem.2010.02.001. View

Kwiatkowski D, Manning B . Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum Mol Genet. 2005; 14 Spec No. 2:R251-8. DOI: 10.1093/hmg/ddi260. View

Folkes A, Ahmadi K, Alderton W, Alix S, Baker S, Box G . The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer . J Med Chem. 2008; 51(18):5522-32. DOI: 10.1021/jm800295d. View

Pan H, Agate D, King B, Wu M, Roderick S, Leiter E . A polymorphism in New Zealand inbred mouse strains that inactivates phosphatidylcholine transfer protein. FEBS Lett. 2006; 580(25):5953-8. PMC: 1693963. DOI: 10.1016/j.febslet.2006.09.066. View

Wu M, Hyogo H, Yadav S, Novikoff P, Cohen D . Impaired response of biliary lipid secretion to a lithogenic diet in phosphatidylcholine transfer protein-deficient mice. J Lipid Res. 2004; 46(3):422-31. DOI: 10.1194/jlr.M400387-JLR200. View

Shishova E, Stoll J, Ersoy B, Shrestha S, Scapa E, Li Y . Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet-induced hepatic glucose production. Hepatology. 2011; 54(2):664-74. PMC: 3144994. DOI: 10.1002/hep.24393. View

Garami A, Zwartkruis F, Nobukuni T, Joaquin M, Roccio M, Stocker H . Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell. 2003; 11(6):1457-66. DOI: 10.1016/s1097-2765(03)00220-x. View

Scapa E, Pocai A, Wu M, Gutierrez-Juarez R, Glenz L, Kanno K . Regulation of energy substrate utilization and hepatic insulin sensitivity by phosphatidylcholine transfer protein/StarD2. FASEB J. 2008; 22(7):2579-90. DOI: 10.1096/fj.07-105395. View

Alessi D, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P . Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996; 15(23):6541-51. PMC: 452479. View

10.

Huang J, Manning B . The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J. 2008; 412(2):179-90. PMC: 2735030. DOI: 10.1042/BJ20080281. View

11.

Kang H, Kanno K, Scapa E, Cohen D . Regulatory role for phosphatidylcholine transfer protein/StarD2 in the metabolic response to peroxisome proliferator activated receptor alpha (PPARalpha). Biochim Biophys Acta. 2010; 1801(4):496-502. PMC: 2826570. DOI: 10.1016/j.bbalip.2009.12.013. View

12.

Manning B, Tee A, Logsdon M, Blenis J, Cantley L . Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell. 2002; 10(1):151-62. DOI: 10.1016/s1097-2765(02)00568-3. View

13.

Stambolic V, Suzuki A, de la Pompa J, Brothers G, Mirtsos C, Sasaki T . Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998; 95(1):29-39. DOI: 10.1016/s0092-8674(00)81780-8. View

14.

Wu J, Tseng Y, Xu C, Neubert T, White M, Hubbard S . Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2. Nat Struct Mol Biol. 2008; 15(3):251-8. DOI: 10.1038/nsmb.1388. View

15.

Kanno K, Wu M, Agate D, Fanelli B, Wagle N, Scapa E . Interacting proteins dictate function of the minimal START domain phosphatidylcholine transfer protein/StarD2. J Biol Chem. 2007; 282(42):30728-36. DOI: 10.1074/jbc.M703745200. View

16.

Wu M, Boylan M, Cohen D . Cloning and gene structure of rat phosphatidylcholine transfer protein, Pctp. Gene. 1999; 235(1-2):111-20. DOI: 10.1016/s0378-1119(99)00204-8. View

17.

Saltiel A, Kahn C . Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001; 414(6865):799-806. DOI: 10.1038/414799a. View

18.

Wirtz K . Phospholipid transfer proteins. Annu Rev Biochem. 1991; 60:73-99. DOI: 10.1146/annurev.bi.60.070191.000445. View

19.

Dibble C, Asara J, Manning B . Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol. 2009; 29(21):5657-70. PMC: 2772744. DOI: 10.1128/MCB.00735-09. View

20.

Copps K, White M . Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia. 2012; 55(10):2565-2582. PMC: 4011499. DOI: 10.1007/s00125-012-2644-8. View