Functional properties of leptin receptor isoforms containing the gln-->pro extracellular domain mutation of the fatty rat

Endocrinology. 1998 Sep;139(9):3681-90. doi: 10.1210/endo.139.9.6168.

Abstract

Mutations of the leptin receptor have been found to cause obesity in rodents. The fa mutation that is responsible for obesity in Zucker rats is a missense mutation (269 gln-->pro) in the extracellular domain of the leptin receptor. We have characterized the effects of this mutation on the two major isoforms of the leptin receptor, Ob-Rb and Ob-Ra, by studying cell-surface expression, leptin binding affinity, signaling capacity, and receptor-mediated internalization and degradation of leptin in transfected mammalian cell lines. Both Ob-Rb(269 gln-->pro) and Ob-Ra(269 gln-->pro) have decreased cell-surface expression and decreased leptin binding affinity. Ob-Rb(269 gln-->pro) was shown to have defective signaling to the JAK-STAT pathway and markedly diminished ability to activate transcription of the egr-1 promoter. Constitutive ligand-independent activation of Ob-Rb(269 gln-->pro) was observed for activation of egr-1-luc but only under conditions when JAK2 was coexpressed with Ob-Rb(269 gln-->pro), Finally, Ob-Ra(269 gln-->pro) has an increased ability to internalize leptin but is less efficient at degrading leptin, as compared with Ob-Ra. In conclusion, both Ob-Ra(269 gln-->pro) and Ob-Rb(269 gln-->pro) have multiple functional defects.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding, Competitive
  • CHO Cells
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology*
  • Cricetinae
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Early Growth Response Protein 1
  • Humans
  • Immediate-Early Proteins*
  • Isomerism
  • Janus Kinase 2
  • Leptin
  • Mice
  • Mutation / physiology*
  • Obesity / genetics*
  • Obesity / physiopathology*
  • Oxidation-Reduction
  • Phosphorylation / drug effects
  • Promoter Regions, Genetic / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Proteins / pharmacology
  • Proto-Oncogene Proteins*
  • Rats
  • Rats, Zucker / genetics*
  • Rats, Zucker / physiology*
  • Receptors, Cell Surface*
  • Receptors, Leptin
  • Recombinant Proteins
  • STAT3 Transcription Factor
  • Trans-Activators / physiology
  • Transcription Factors / genetics
  • Tyrosine / metabolism

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Egr1 protein, rat
  • Immediate-Early Proteins
  • LEPR protein, human
  • Leptin
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, Cell Surface
  • Receptors, Leptin
  • Recombinant Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Stat3 protein, rat
  • Trans-Activators
  • Transcription Factors
  • leptin receptor, mouse
  • Tyrosine
  • Protein-Tyrosine Kinases
  • JAK2 protein, human
  • Jak2 protein, mouse
  • Jak2 protein, rat
  • Janus Kinase 2