Divergent Signaling Capacities of the Long and Short Isoforms of the Leptin Receptor

Bjørbæk, Christian; Uotani, Shigeo; da Silva, Barbara; Flier, Jeffrey S.

doi:10.1074/jbc.272.51.32686

Cited by 890Regulation of Appetite and ObesityCytokine Signaling Pathways and InteractionsAdipokines, Inflammation, and Metabolic Diseases

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Divergent Signaling Capacities of the Long and Short Isoforms of the Leptin Receptor

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Bjørbæk, Christian, Uotani, Shigeo, da Silva, Barbara, Flier, Jeffrey S.·1997·Journal of Biological Chemistry

DOI 10.1074/jbc.272.51.32686

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Abstract

Leptin receptors include a long form (OBRl) with 302 cytoplasmic residues that is presumed to mediate most or all of leptins signaling, and several short forms, including one (OBRs) that has 34 cytoplasmic residues, is widely expressed, and is presumed not to signal but to mediate transport or clearance of leptin. We studied the abilities of these two receptor isoforms to mediate signaling in transfected cells. In response to leptin, OBRl, but not OBRs, underwent tyrosine phosphorylation that was enhanced by co-expression with JAK2. In cells expressing receptors and JAK2, both OBRs and OBRl mediated leptin-dependent tyrosine phosphorylation of JAK2, and this was abolished with OBRs when the Box 1 motif was mutated. In cells expressing receptors, JAK2 and IRS-1, leptin induced tyrosine phosphorylation of IRS-1 through OBRs and OBRl. In COS cells expressing hemagglutinin-ERK1 and receptors, leptin increased ERK1 kinase activity through OBRl, with the magnitude increased by co-expression of JAK1 or JAK2, and to a lesser degree through OBRs, despite greater receptor expression. In stable Chinese hamster ovary cell lines expressing OBRs or OBRl, leptin stimulated endogenous ERK2 phosphorylation. Whereas leptin stimulated tyrosine phosphorylation of hemagglutinin-STAT3 and induction of a c-fos luciferase reporter plasmid through OBRl, OBRs was without effect in these assays. In conclusion, OBRl is capable of signaling to IRS-1 and mitogen-activated protein kinase via JAK, in addition to activating STAT pathways. Although substantially weaker than OBRl, OBRs is capable of mediating signal transduction via JAK, but these activities are of as yet unknown significance for leptin biology in vivo.

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Phosphorylation of Tyr1138 recruits STAT3, which is phosphorylated by Jak2, dimerizes, translocates to the nucleus, and functions as a transcription factor.
“phosphorylation of Tyr1138 recruits signal transduction and activator of transcription-3 (STAT3), which is then itself phosphorylated on tyrosine residues by Jak2 allowing it to dimerize and translocate to the nucleus where it functions as a transcription factor (6, 23, 186).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [23]

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Authors: Bjørbæk, C., Uotani, S., da Silva, B., & Flier, J. S.
Affiliations: Beth Israel Deaconess Medical Center (US)
Corresponding author: Flier, Jeffrey S.
ORCID: Flier, Jeffrey S.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1997-12
Volume: 272
Issue: 51
Pages: 32686-32695
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.272.51.32686
OpenAlex: W2137736712
Cited by: 890
References: 67
Citations by year: 2026: 5 · 2025: 7 · 2024: 14 · 2023: 15 · 2022: 9 · 2021: 20 · 2020: 19 · 2019: 17 · 2018: 23 · 2017: 18 · 2016: 28 · 2015: 34 · 2014: 33 · 2013: 41 · 2012: 32
FWCI: 8.73
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 8348 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Eli Lilly and Company
Universität Basel
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases (DK28082)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Keywords: leptin receptor, receptor isoforms, leptin signaling, JAK2, JAK1, IRS-1, ERK1/2, mitogen-activated protein kinase, STAT3, tyrosine phosphorylation, c-fos, signal transduction
MeSH terms: Animals, Carrier Proteins, Cloning, Molecular, DNA-Binding Proteins, Cricetinae, Humans, Obesity, Phosphoproteins, Phosphorylation, Receptors, Cell Surface, Transcription, Genetic, Tyrosine, Signal Transduction, Trans-Activators, CHO Cells, Proto-Oncogene Proteins c-fos, DNA, Complementary, COS Cells, STAT3 Transcription Factor, Mice, Receptors, Leptin, Insulin Receptor Substrate Proteins

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Divergent Signaling Capacities of the Long and Short Isoforms of the Leptin Receptor

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