SOCS3 Mediates Feedback Inhibition of the Leptin Receptor via Tyr985
Open accessAbstract
During leptin signaling, each of the phosphorylated tyrosine residues on the long form of the leptin receptor (LRb) mediates distinct signals. Phosphorylated Tyr(1138) binds STAT3 to mediate its tyrosine phosphorylation and transcriptional activation, while phosphorylated Tyr(985) binds the tyrosine phosphatase SHP-2 and reportedly mediates both activation of ERK kinases and inhibition of LRb-mediated STAT3 activation. We show here that although mutation of Tyr(985) does not alter STAT3 signaling by erythropoietin receptor-LRb (ELR) chimeras in transfected 293 cells at short times of stimulation, this mutation enhances STAT3 signaling at longer times of stimulation (>6 h). These data suggest that Tyr(985) may mediate feedback inhibition of LRb signaling by an LRb-induced LRb inhibitor, such as SOCS3. Indeed, SOCS3 binds specifically to phosphorylated Tyr(985) of LRb, and SOCS3 fails to inhibit transcription by ELR following mutation of Tyr(985), suggesting that SOCS3 inhibits LRb signaling by binding to phosphorylated Tyr(985). Additionally, overexpression of SOCS3, but not SHP-2, impairs ELR signaling, and the overexpression of SHP-2 blunts SOCS3-mediated inhibition of ELR signaling. Thus, our data suggest that in addition to mediating SHP-2 binding and ERK activation during acute stimulation, Tyr(985) of LRb mediates feedback inhibition of LRb signaling by binding to LRb-induced SOCS3.
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Phosphorylation of Tyr985 recruits SHP-2 to LepRb, leading to ERK pathway activation in cultured cells and recruitment of SOCS-3.
“Phosphorylation of Tyr985 recruits SH2-domain-containing phosphatase-2 (SHP-2) to LepRb, leading to the activation of the extracellular signal regulated (ERK) signaling pathway in cultured cells, as well as the recruitment of suppressor of cytokine signaling-3 (SOCS-3), a negative regulator of LepRb signaling (6, 21, 22).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [22]
Tyr985 attenuates leptin action in vivo, presumably by serving as the SOCS-3 binding site.
“These results support data from cultured cells (22) suggesting that Tyr985 attenuates leptin action in vivo, presumably by serving as the SOCS-3 binding site (24).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [22]
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BackgroundResultMünzberg, H., Huo, L., Nillni, E. A., Hollenberg, A. N., & Bjørbæk, C. (2003) · Endocrinology · doi:10.1210/en.2002-221037 · Cited by 328 · see citing works
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Knight, Z. A., Hannan, K. S., Greenberg, M. L., & Friedman, J. M. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011376 · Cited by 311 · see citing works
Sweeney, G. (2002) · Cellular Signalling · doi:10.1016/s0898-6568(02)00006-2 · Cited by 271 · see citing works
Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats
Pocai, A. (2006) · Journal of Clinical Investigation · doi:10.1172/jci26640 · Cited by 211 · see citing works
Ernst, M. B., Wunderlich, C. M., Hess, S., Paehler, M., Mesaros, A., Koralov, S. B., Kleinridders, A., Husch, A., Münzberg, H., Hampel, B., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.5712-08.2009 · Cited by 185 · see citing works
Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function
Björnholm, M., Münzberg, H., Leshan, R. L., Villanueva, E. C., Bates, S. H., Louis, G. W., Jones, J. C., Ishida-Takahashi, R., Bjørbaek, C., & Myers, M. G. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30688 · Cited by 183 · see citing works
Self-citationReed, A. S., Unger, E. K., Olofsson, L. E., Piper, M. L., Myers, M. G., & Xu, A. W. (2010) · Diabetes · doi:10.2337/db09-1024 · Cited by 176 · see citing works
Self-citationGong, Y., Ishida-Takahashi, R., Villanueva, E. C., Fingar, D. C., Münzberg, H., & Myers, M. G. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702838200 · Cited by 173 · see citing works
Self-citationBates, S. H., Kulkarni, R. N., Seifert, M., & Myers, M. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.02.001 · Cited by 173 · see citing works
Self-citationObesity, leptin, and Alzheimer's disease
Lee, E. B. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2011.06274.x · Cited by 126 · see citing works
Vagal control of satiety and hormonal regulation of appetite
Owyang, C., & Heldsinger, A. (2011) · Journal of Neurogastroenterology and Motility · doi:10.5056/jnm.2011.17.4.338 · Cited by 87 · see citing works
Development of Diabesity in Mice with Neuronal Deletion of Shp2 Tyrosine Phosphatase
Krajewska, M., Banares, S., Zhang, E. E., Huang, X., Scadeng, M., Jhala, U. S., Feng, G.-S., & Krajewski, S. (2008) · The American Journal of Pathology · doi:10.2353/ajpath.2008.070594 · Cited by 72 · see citing works
Leptin in hepatocellular carcinoma
Wang, S.-N. (2010) · World Journal of Gastroenterology · doi:10.3748/wjg.v16.i46.5801 · Cited by 59 · see citing works
Structural Basis for Phosphotyrosine Recognition by Suppressor of Cytokine Signaling-3
Bergamin, E., Wu, J., & Hubbard, S. R. (2006) · Structure · doi:10.1016/j.str.2006.06.011 · Cited by 60 · see citing works
LRb signals act within a distributed network of leptin‐responsive neurones to mediate leptin action
Leinninger, G. M., & Myers, M. G. (2008) · Acta Physiologica · doi:10.1111/j.1748-1716.2007.01784.x · Cited by 56 · see citing works
Self-citationMolecular Targets for Obesity Therapy in the Brain
Obici, S. (2009) · Endocrinology · doi:10.1210/en.2009-0409 · Cited by 45 · see citing works
Robertson, S., Ishida-Takahashi, R., Tawara, I., Hu, J., Patterson, C. M., Jones, J. C., Kulkarni, R. N., & Myers, M. G. (2010) · Diabetes · doi:10.2337/db09-1556 · Cited by 30 · see citing works
Self-citationKempf, K., Röhling, M., Banzer, W., Braumann, K. M., Halle, M., Schaller, N., McCarthy, D., Predel, H. G., Schenkenberger, I., Tan, S., et al. (2022) · Nutrients · doi:10.3390/nu14122537 · Cited by 14 · see citing works
do Carmo, J. M., da Silva, A. A., Freeman, J. N., Wang, Z., Moak, S. P., Hankins, M. W., Drummond, H. A., & Hall, J. E. (2018) · Hypertension · doi:10.1161/hypertensionaha.118.11127 · Cited by 11 · see citing works
- Authors
- Bjørbæk, C., Lavery, H. J., Bates, S. H., Olson, R. K., Davis, S. M., Flier, J. S., & Myers, M. G.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Joslin Diabetes Center (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-12
- Volume
- 275
- Issue
- 51
- Pages
- 40649-40657
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2168692939
- Cited by
- 537
- References
- 65
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 12 · 2023: 9 · 2022: 16 · 2021: 19 · 2020: 25 · 2019: 14 · 2018: 21 · 2017: 18 · 2016: 18 · 2015: 19 · 2014: 34 · 2013: 30 · 2012: 29
- FWCI
- 9.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-R37-28082, DKR0156731)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- SOCS3, leptin receptor, product inhibition, STAT3 signaling, SHP2, receptor tyrosine phosphorylation, ERK activation, transcriptional activation
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Carrier Proteins, Cell Line, Feedback, Humans, Proteins, Receptors, Cell Surface, Repressor Proteins, Transcription Factors, Tyrosine, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Receptors, Leptin
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