Constitutive and impaired signaling of leptin receptors containing the Gln --> Pro extracellular domain fatty mutation.
Leptin (OB), an adipocyte-secreted circulating hormone, and its receptor (OB-R) are key components of an endocrine loop that regulates mammalian body weight. In this report we have analyzed signal transduction activities of OB-R containing the fatty mutation [OB-R(fa)], a single amino acid substitution at position 269 (Gln --> Pro) in the OB-R extracellular domain that results in the obese phenotype of the fatty rat. We find that this mutant receptor exhibits both ligand-independent transcriptional activation via interleukin 6 and hematopoietin receptor response elements and ligand-independent activation of signal transducer and activator of transcription (STAT) proteins 1 and 3. However, OB-R(fa) is unable to constitutively activate STAT5B and is highly impaired for ligand induced activation of STAT5B compared with OB-R(wt). Introduction of the fatty mutation into a OB-R/G-CSF-R chimera generates a receptor with constitutive character that is similar but distinct from that of OB-R(fa). Constitutive mutant OB-R(fa) receptor signaling is repressed by coexpression of OB-R(wt). The implications of an extracellular domain amino acid substitution generating a cytokine receptor with a partially constitutive phenotype are discussed both in terms of the mechanism of OB-R triggering and the biology of the fatty rat.
White
D W
DW
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Wang
D W
DW
Chua
S C
SC
Morgenstern
J P
JP
Leibel
R L
RL
Baumann
H
H
Tartaglia
L A
LA
D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005998:Glycine / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011392:Proline / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D054411:Receptors, Leptin; D015398:Signal Transduction
D002352:Carrier Proteins; D011956:Receptors, Cell Surface; D018121:Receptors, Cytokine; D054411:Receptors, Leptin; D011392:Proline; D005998:Glycine