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Cell Cycle Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kccy20
Feedback regulation of mTORC1 by Grb10 in metabolism and beyond a
Bilian Liu & Feng Liu
ab
a
Metabolic Syndrome Research Center; Key Laboratory of Diabetes Immunology; Ministry of Education; National Clinic Research Center for Metabolic Diseases; The Xiangya Second Hospital; Central South University; Changsha, Hunan, China b
Department of Pharmacology; University of Texas Health Science Center at San Antonio; San Antonio, TX USA Published online: 30 Oct 2014.
Click for updates To cite this article: Bilian Liu & Feng Liu (2014) Feedback regulation of mTORC1 by Grb10 in metabolism and beyond, Cell Cycle, 13:17, 2643-2644, DOI: 10.4161/15384101.2014.954221 To link to this article: http://dx.doi.org/10.4161/15384101.2014.954221
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
FEATURE Cell Cycle 13:17, 2643--2644; September 1, 2014; © 2014 Taylor & Francis Group, LLC
Feedback regulation of mTORC1 by Grb10 in metabolism and beyond Bilian Liu1 and Feng Liu1,2,*
Downloaded by [Northwestern University] at 17:16 30 January 2015
1
Metabolic Syndrome Research Center; Key Laboratory of Diabetes Immunology; Ministry of Education; National Clinic Research Center for Metabolic Diseases; The Xiangya Second Hospital; Central South University; Changsha, Hunan, China; 2Department of Pharmacology; University of Texas Health Science Center at San Antonio; San Antonio, TX USA
Obesity, which results from imbalanced energy intake and energy expenditure, is well recognized as a key risk factor for various metabolic and cardiovascular diseases as well as certain types of cancer. Obesity is characterized by excessive expansion of white adipose tissue (WAT) and impaired thermogenic function in brown adipose tissue (BAT). In addition to WAT and BAT, recent studies reveal the presence of a subset of adipocytes in WAT that, in response to environmental or hormonal stimulation, become “brown-like” or “beige” cells. Over the past decade, great progress has been made on our understanding of the anti-obesity benefits of the beige cells and the mechanisms regulating the “beigeing” process at the transcriptional level.1 However, the upstream signaling pathways regulating the transcriptional machinery involved in the regulation of adipogenesis, thermogenesis, and adipocyte function remain to be fully characterized. Accumulating evidence has been obtained in recent years to indicate that the mechanistic target of rapamycin complex 1 (mTORC1) plays a key role in the regulation of fat metabolism. Inhibition of the mTORC1 signaling pathway promotes triacylglycerol lipolysis, increases free fatty acid release, enhances uncoupling protein 1 (UCP1) expression and thermogenesis, and improves obesity, inflammation and insulin resistance.2 The precise mechanisms regulating mTORC1 signaling and action, especially in vivo, remain elusive. Two recent studies showed that mTOR directly phosphorylates Grb10 (Growth factor receptor-bound
protein-10),3,4 a Src homology 2 (SH2)and pleckstrin homology (PH)-domain containing adaptor protein originally identified by us and others as a negative regulator of insulin and IGF-1 signaling.5 Grb10 expression in adipose tissues is greatly induced by cold exposure. In addition, fatspecific knockout of Grb10 suppressed lipolytic and thermogenic gene expression, reduced energy expenditure, and exacerbated diet-induced obesity and insulin resistance,6 uncovering Grb10 as an important regulator of adipose tissue metabolism and energy homeostasis. How does Grb10 regulate lipid metabolism and thermogenesis in vivo? Grb10deficiency led to a marked increase in S6 kinase phosphorylation in adipose tissues,6
suggesting that Grb10 may promote lipolysis and thermogenesis by negative regulation of the mTORC1 signaling pathway. Consistent with this, overexpression of Grb10 inhibits not only insulin- but also leucine-stimulated S6 kinase phosphorylation,6 revealing that Grb10 is able to inhibit the mTORC1 signaling pathway via a PI3K/Akt-independent mechanism. Grb10 interacts with both the insulin receptor and raptor, a positive regulator of mTORC1, and the interaction is inhibited or stimulated, respectively, by mTOR-mediated phosphorylation, demonstrating a feedback mechanism to regulate the mTORC1 signaling pathway6 and (Fig. 1). The identification of Grb10 as a critical regulator of mTORC1 signaling,
Insulin Insulin
receptor
PTEN
Grb10 IRS-1/2
PI3K Akt
mTOR Cell growth Cell cycle, …
Grb10 -P
Raptor Lipolysis Thermogenesis
mTOR (inacve) Grb10 -P Raptor
Figure 1. Feedback regulation of PI3K/Akt/mTORC1 signaling by Grb10. Grb10 inhibits PI3K/Akt/ mTORC1 pathway by binding to tyrosine phosphorylated insulin receptor (IR). Sustained activation of the mTORC1 leads to Grb10 phosphorylation at Ser501/503, which promotes Grb10 dissociation from the IR to interact with raptor, an activator of mTOR. The interaction of Grb10 with raptor prevents raptor from binding to mTOR and thus suppresses mTORC1 signaling. By phosphorylationdependent interaction with IR and raptor, Grb10 dynamically regulates the signaling pathways downstream of IR, thus selectively regulating mTORC1-mediated biological events such as lipid metabolism, cell growth, and cell cycle.
*Correspondence to: Feng Liu; Email: [email protected] Submitted: 07/28/2014; Accepted: 07/28/2014 http://dx.doi.org/10.4161/15384101.2014.954221 Comment on: Liu M, et al. Cell Metab 2014; 19(6):967-80; http://dx.doi.org/10.1016/j.cmet.2014.03.018
www.landesbioscience.com
Cell Cycle
2643
Downloaded by [Northwestern University] at 17:16 30 January 2015
lipid metabolism, thermogenesis, and the development of beige fat should shed new light on the development of pharmacological tools to treat obesity and obesityinduced metabolic diseases. It should be noted that in addition to functioning as a central regulator of protein synthesis and lipid metabolism, the mTORC1 signaling pathway also plays key roles in many other important biological processes such as cell growth, proliferation, and cell cycle.7 Thus, it is not surprising that this signaling is subjected to tight regulation of multiple oncogenes and tumor suppressors. References 1.
2.
Rosen ED, et al. Cell 2014; 156(1-2):20–44; PMID:24439368; http://dx.doi.org/10.1016/j.cell. 2013 Lamming DW, et al. Cell metabolism 2013; 18(4): 465–9; PMID:23973332; http://dx.doi.org/10.1016/ j.cmet.2013.08.002
2644
Comprehensive meta-analysis of available microarray data reveals that Grb10 levels are decreased in many tumor types compared to normal tissue counterparts.4 In addition, there is a significant negative correlation between Grb10 and PTEN expression in tumor samples.4 Thus, Grb10 deficiency, which results in abnormal PI3K/Akt/mTORC1 activation, might provide growth and survival advantages for tumor cells, leading to cancer development. The finding that Grb10 negatively regulates the PI3K/Akt/mTORC1 signaling pathway via a phosphorylation-dependent
mechanism suggests that Grb10 might be a tumor suppressor that is regulated by mTORC1. Since abnormal activation of the PI3K/Akt/mTORC1 signaling pathway may promote tumors or cancer, enhancing the expression levels of Grb10 may provide a promising new treatment in cancer therapy. Further investigations on tissue-specific roles of Grb10, its expression, and the mechanisms of Grb10 action should thus guide new approaches for obesity-related metabolic diseases and cancer.
3.
6.
4.
5.
Hsu PP, et al. Science 2011; 332(6035):1317–22; PMID:21659604; http://dx.doi.org/10.1126/science. 1199498 Yu Y, et al. Science 2011; 332(6035):1322–6; PMID:21659605; http://dx.doi.org/10.1126/science. 1199484 Lim MA, et al. Front Biosci 2004; 9:387–403; PMID:14766376.
Cell Cycle
7.
Liu M, et al. Cell metabolism 2014; 19(6):967–80; PMID:24746805; http://dx.doi.org/10.1016/j.cmet. 2014.03.018 Kelsey I, et al. Science signaling 2013; 6(294): pe31; PMID:24065143; http://dx.doi.org/10.1126/ scisignal.2004632
Volume 13 Issue 17
Cell Cycle Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kccy20
Feedback regulation of mTORC1 by Grb10 in metabolism and beyond a
Bilian Liu & Feng Liu
ab
a
Metabolic Syndrome Research Center; Key Laboratory of Diabetes Immunology; Ministry of Education; National Clinic Research Center for Metabolic Diseases; The Xiangya Second Hospital; Central South University; Changsha, Hunan, China b
Department of Pharmacology; University of Texas Health Science Center at San Antonio; San Antonio, TX USA Published online: 30 Oct 2014.
Click for updates To cite this article: Bilian Liu & Feng Liu (2014) Feedback regulation of mTORC1 by Grb10 in metabolism and beyond, Cell Cycle, 13:17, 2643-2644, DOI: 10.4161/15384101.2014.954221 To link to this article: http://dx.doi.org/10.4161/15384101.2014.954221
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
FEATURE Cell Cycle 13:17, 2643--2644; September 1, 2014; © 2014 Taylor & Francis Group, LLC
Feedback regulation of mTORC1 by Grb10 in metabolism and beyond Bilian Liu1 and Feng Liu1,2,*
Downloaded by [Northwestern University] at 17:16 30 January 2015
1
Metabolic Syndrome Research Center; Key Laboratory of Diabetes Immunology; Ministry of Education; National Clinic Research Center for Metabolic Diseases; The Xiangya Second Hospital; Central South University; Changsha, Hunan, China; 2Department of Pharmacology; University of Texas Health Science Center at San Antonio; San Antonio, TX USA
Obesity, which results from imbalanced energy intake and energy expenditure, is well recognized as a key risk factor for various metabolic and cardiovascular diseases as well as certain types of cancer. Obesity is characterized by excessive expansion of white adipose tissue (WAT) and impaired thermogenic function in brown adipose tissue (BAT). In addition to WAT and BAT, recent studies reveal the presence of a subset of adipocytes in WAT that, in response to environmental or hormonal stimulation, become “brown-like” or “beige” cells. Over the past decade, great progress has been made on our understanding of the anti-obesity benefits of the beige cells and the mechanisms regulating the “beigeing” process at the transcriptional level.1 However, the upstream signaling pathways regulating the transcriptional machinery involved in the regulation of adipogenesis, thermogenesis, and adipocyte function remain to be fully characterized. Accumulating evidence has been obtained in recent years to indicate that the mechanistic target of rapamycin complex 1 (mTORC1) plays a key role in the regulation of fat metabolism. Inhibition of the mTORC1 signaling pathway promotes triacylglycerol lipolysis, increases free fatty acid release, enhances uncoupling protein 1 (UCP1) expression and thermogenesis, and improves obesity, inflammation and insulin resistance.2 The precise mechanisms regulating mTORC1 signaling and action, especially in vivo, remain elusive. Two recent studies showed that mTOR directly phosphorylates Grb10 (Growth factor receptor-bound
protein-10),3,4 a Src homology 2 (SH2)and pleckstrin homology (PH)-domain containing adaptor protein originally identified by us and others as a negative regulator of insulin and IGF-1 signaling.5 Grb10 expression in adipose tissues is greatly induced by cold exposure. In addition, fatspecific knockout of Grb10 suppressed lipolytic and thermogenic gene expression, reduced energy expenditure, and exacerbated diet-induced obesity and insulin resistance,6 uncovering Grb10 as an important regulator of adipose tissue metabolism and energy homeostasis. How does Grb10 regulate lipid metabolism and thermogenesis in vivo? Grb10deficiency led to a marked increase in S6 kinase phosphorylation in adipose tissues,6
suggesting that Grb10 may promote lipolysis and thermogenesis by negative regulation of the mTORC1 signaling pathway. Consistent with this, overexpression of Grb10 inhibits not only insulin- but also leucine-stimulated S6 kinase phosphorylation,6 revealing that Grb10 is able to inhibit the mTORC1 signaling pathway via a PI3K/Akt-independent mechanism. Grb10 interacts with both the insulin receptor and raptor, a positive regulator of mTORC1, and the interaction is inhibited or stimulated, respectively, by mTOR-mediated phosphorylation, demonstrating a feedback mechanism to regulate the mTORC1 signaling pathway6 and (Fig. 1). The identification of Grb10 as a critical regulator of mTORC1 signaling,
Insulin Insulin
receptor
PTEN
Grb10 IRS-1/2
PI3K Akt
mTOR Cell growth Cell cycle, …
Grb10 -P
Raptor Lipolysis Thermogenesis
mTOR (inacve) Grb10 -P Raptor
Figure 1. Feedback regulation of PI3K/Akt/mTORC1 signaling by Grb10. Grb10 inhibits PI3K/Akt/ mTORC1 pathway by binding to tyrosine phosphorylated insulin receptor (IR). Sustained activation of the mTORC1 leads to Grb10 phosphorylation at Ser501/503, which promotes Grb10 dissociation from the IR to interact with raptor, an activator of mTOR. The interaction of Grb10 with raptor prevents raptor from binding to mTOR and thus suppresses mTORC1 signaling. By phosphorylationdependent interaction with IR and raptor, Grb10 dynamically regulates the signaling pathways downstream of IR, thus selectively regulating mTORC1-mediated biological events such as lipid metabolism, cell growth, and cell cycle.
*Correspondence to: Feng Liu; Email: [email protected] Submitted: 07/28/2014; Accepted: 07/28/2014 http://dx.doi.org/10.4161/15384101.2014.954221 Comment on: Liu M, et al. Cell Metab 2014; 19(6):967-80; http://dx.doi.org/10.1016/j.cmet.2014.03.018
www.landesbioscience.com
Cell Cycle
2643
Downloaded by [Northwestern University] at 17:16 30 January 2015
lipid metabolism, thermogenesis, and the development of beige fat should shed new light on the development of pharmacological tools to treat obesity and obesityinduced metabolic diseases. It should be noted that in addition to functioning as a central regulator of protein synthesis and lipid metabolism, the mTORC1 signaling pathway also plays key roles in many other important biological processes such as cell growth, proliferation, and cell cycle.7 Thus, it is not surprising that this signaling is subjected to tight regulation of multiple oncogenes and tumor suppressors. References 1.
2.
Rosen ED, et al. Cell 2014; 156(1-2):20–44; PMID:24439368; http://dx.doi.org/10.1016/j.cell. 2013 Lamming DW, et al. Cell metabolism 2013; 18(4): 465–9; PMID:23973332; http://dx.doi.org/10.1016/ j.cmet.2013.08.002
2644
Comprehensive meta-analysis of available microarray data reveals that Grb10 levels are decreased in many tumor types compared to normal tissue counterparts.4 In addition, there is a significant negative correlation between Grb10 and PTEN expression in tumor samples.4 Thus, Grb10 deficiency, which results in abnormal PI3K/Akt/mTORC1 activation, might provide growth and survival advantages for tumor cells, leading to cancer development. The finding that Grb10 negatively regulates the PI3K/Akt/mTORC1 signaling pathway via a phosphorylation-dependent
mechanism suggests that Grb10 might be a tumor suppressor that is regulated by mTORC1. Since abnormal activation of the PI3K/Akt/mTORC1 signaling pathway may promote tumors or cancer, enhancing the expression levels of Grb10 may provide a promising new treatment in cancer therapy. Further investigations on tissue-specific roles of Grb10, its expression, and the mechanisms of Grb10 action should thus guide new approaches for obesity-related metabolic diseases and cancer.
3.
6.
4.
5.
Hsu PP, et al. Science 2011; 332(6035):1317–22; PMID:21659604; http://dx.doi.org/10.1126/science. 1199498 Yu Y, et al. Science 2011; 332(6035):1322–6; PMID:21659605; http://dx.doi.org/10.1126/science. 1199484 Lim MA, et al. Front Biosci 2004; 9:387–403; PMID:14766376.
Cell Cycle
7.
Liu M, et al. Cell metabolism 2014; 19(6):967–80; PMID:24746805; http://dx.doi.org/10.1016/j.cmet. 2014.03.018 Kelsey I, et al. Science signaling 2013; 6(294): pe31; PMID:24065143; http://dx.doi.org/10.1126/ scisignal.2004632
Volume 13 Issue 17
