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Divergent roles of SHP-2 in ERK activation by leptin receptors

C Bjørbaek1, R M Buchholz, S M Davis

  • 1Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

The Journal of Biological Chemistry
|November 22, 2000
PubMed

Insights

Protein tyrosine phosphatase SHP-2 positively regulates leptin signaling by activating ERK phosphorylation. Both SHP-2

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Endocrinology

Background:

  • Leptin signaling regulates appetite and metabolism.
  • The role of protein tyrosine phosphatase SHP-2 in leptin pathways is not fully understood.

Purpose of the Study:

  • To investigate the specific regulatory role of SHP-2 in leptin-induced ERK activation.
  • To elucidate the mechanisms by which SHP-2 influences leptin receptor signaling.

Main Methods:

  • Utilized dominant-negative strategies in transfected cells to study SHP-2 function.
  • Examined leptin-stimulated ERK phosphorylation and egr-1 promoter activity.
  • Analyzed signaling through leptin receptors (ObRb and ObRa) with mutated intracellular domains.

Main Results:

  • Catalytically inactive SHP-2 blocked leptin-stimulated ERK phosphorylation via ObRb.
  • SHP-2 mutants lacking C-terminal tyrosines partially inhibited ERK phosphorylation.
  • Two distinct pathways for ERK activation were identified, one independent of the ObRb intracellular domain and another dependent on ObRb tyrosine 985.
  • SHP-2 phosphatase activity was essential for both pathways; ObRb Tyr-985 signaling also required SHP-2 tyrosine phosphorylation.

Conclusions:

  • SHP-2 acts as a positive regulator of leptin-induced ERK activation.
  • Both the phosphatase activity and adaptor function of SHP-2 are critical for leptin signaling.
  • Leptin signaling involves distinct pathways mediated by ObRb, with SHP-2 playing a key role in their activation.

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