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.
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, signaling-defective 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 homo-oligomerization 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).
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Millennium Pharmaceuticals, Cambridge, Massachusetts 02139-2406, USA.
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D000595:Amino Acid Sequence; D001704:Biopolymers; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D000939:Epitopes / Q000378:metabolism; D006801:Humans; D053616:Janus Kinase 3; D020738:Leptin; D008024:Ligands; D020033:Protein Isoforms / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D015398:Signal Transduction
D001704:Biopolymers; D002352:Carrier Proteins; D000939:Epitopes; C515448:LEPR protein, human; D020738:Leptin; D008024:Ligands; D020033:Protein Isoforms; D011506:Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3