Evidence for ligand-independent homo-oligomerization of leptin receptor (OB-R) isoforms: A proposed mechanism permitting productive long-form signaling in the presence of excess short-form expression
✍ Scribed by David W. White; Louis A. Tartaglia
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 128 KB
- Volume
- 73
- Category
- Article
- ISSN
- 0730-2312
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✦ Synopsis
The adipocyte secreted hormone leptin (OB) and its receptor (OB-R) are key regulators of mammalian body weight homeostasis. Two predominant isoforms of OB-R have been described: long form (OB-R L ) characterized as a signal transducing receptor that is highly expressed in specific nuclei of the hypothalamus; and a short, signalingdefective form (OB-R S ) of indeterminate function that is ubiquitously expressed throughout the body. Receptor chimera studies indicate that OB-R L signals via homo-oligomers. However, co-expression experiments have demonstrated that signaling by OB-R L is only marginally susceptible to dominant negative suppression by OB-R S . In the present study we have used receptor epitope tagging to analyze the ligand-independent and -dependent association properties of OB-R S and OB-R L . We present evidence for ligand-independent homo-oligomerization by both receptor isoforms. Ligand treatment of these complexes does not dramatically augment homo-oligomerization. In contrast, hetero-oligomerization between long and short OB-R cannot be detected in the absence of ligand but can be resolved in the presence of ligand. Deletion and substitution mutagenesis of the OB-R L intracellular domain indicates that ligand-independent homooligomerization by OB-R L is sensitive to reduction in JAK kinase recruitment capability, suggesting that JAK interaction and signaling competency may provide means for isoform specific OB-R sorting. These results are discussed with regard to possible mechanisms permitting efficient leptin-induced signaling by OB-R L in tissues that co-express OB-R S .