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SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985

C Bjorbak1, H J Lavery, S H Bates

  • 1Division of Endocrinology, Beth Israel-Deaconess Medical Center, Harvard Medical School, and Section on Obesity, Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.

The Journal of Biological Chemistry
|October 6, 2000
PubMed

Insights

Leptin receptor (LRb) Tyr(985) initially activates ERK kinases but later inhibits STAT3 signaling by binding SOCS3, revealing a feedback mechanism in leptin signaling pathways.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Endocrinology

Background:

  • Leptin receptor (LRb) signaling involves distinct signals mediated by phosphorylated tyrosine residues.
  • Tyr(1138) phosphorylation activates STAT3, while Tyr(985) phosphorylation is linked to SHP-2 binding, ERK activation, and STAT3 inhibition.

Purpose of the Study:

  • To investigate the role of Tyr(985) in leptin receptor (LRb) signaling, particularly its involvement in feedback inhibition.
  • To elucidate the interaction between LRb, SHP-2, SOCS3, and STAT3 in regulating leptin signaling.

Main Methods:

  • Utilized erythropoietin receptor-LRb (ELR) chimeras in transfected 293 cells.
  • Employed site-directed mutagenesis to study the function of Tyr(985).
  • Assessed STAT3 transcriptional activation and signaling dynamics over time.
  • Investigated protein-protein interactions using binding assays and overexpression studies.

Main Results:

  • Mutation of Tyr(985) enhanced STAT3 signaling at later time points (>6 h), suggesting a feedback inhibitory role.
  • SOCS3 specifically binds to phosphorylated Tyr(985) of LRb.
  • SOCS3 failed to inhibit ELR signaling when Tyr(985) was mutated, confirming its inhibitory mechanism via Tyr(985) binding.
  • Overexpression of SOCS3 impaired ELR signaling, while SHP-2 overexpression blunted SOCS3-mediated inhibition.

Conclusions:

  • Tyr(985) of LRb mediates feedback inhibition of leptin signaling through binding to the LRb-induced inhibitor SOCS3.
  • This mechanism complements the acute roles of Tyr(985) in SHP-2 binding and ERK activation.

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