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Catalytically inactive SHIP2 inhibits proliferation by attenuating PDGF signaling in 3T3-L1 preadipocytes

Yulia Artemenko1, Annemarie Gagnon, Alexander Sorisky

  • 1Chronic Disease Program, Ottawa Health Research Institute and Departments of Medicine and Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.

Journal of Cellular Physiology
|September 25, 2008
PubMed

Insights

A dominant-negative form of SHIP2 (SHIP2 PDR/AAA) surprisingly inhibited preadipocyte proliferation more than wild-type SHIP2 by reducing PDGF receptor signaling and promoting receptor degradation.

Area of Science:

  • Cell Biology
  • Molecular Signaling
  • Metabolic Research

Background:

  • Adipose tissue dysfunction, marked by insulin-resistant adipocytes, can stem from insufficient preadipocyte proliferation or differentiation.
  • Platelet-derived growth factor (PDGF) influences adipose tissue function by stimulating preadipocyte proliferation through PI3K/Akt and Shc/Ras/ERK1/2 pathways.
  • SH2 domain-containing inositol 5-phosphatase 2 (SHIP2) modulates these signaling pathways by dephosphorylating PI(3,4,5)P3 and interacting with Shc.

Purpose of the Study:

  • To investigate the impact of SHIP2 on PDGF-mediated signaling pathways regulating preadipocyte proliferation.
  • To determine the role of SHIP2's 5-phosphatase domain in modulating these signaling routes.

Main Methods:

  • Expression of wild-type or catalytically inactive SHIP2 (PDR/AAA mutant) in 3T3-L1 preadipocytes.
  • Assessment of proliferation rates, levels of phospho-Akt, phospho-ERK1/2, and PDGF receptor (PDGFR).
  • Utilized imatinib, a PDGFR tyrosine kinase inhibitor, to evaluate PDGFR signaling interference and investigated PDGFR ubiquitination and lysosomal degradation.

Main Results:

  • Catalytically inactive SHIP2 (PDR/AAA) significantly inhibited preadipocyte proliferation, more so than wild-type SHIP2.
  • SHIP2 PDR/AAA expression led to reduced levels of phospho-Akt, phospho-ERK1/2, and PDGFR.
  • SHIP2 PDR/AAA impaired PDGFR-dependent mitogenesis, promoting PDGFR ubiquitination and lysosomal degradation independently of c-Cbl.

Conclusions:

  • SHIP2 PDR/AAA attenuates PDGFR signaling, leading to reduced preadipocyte proliferation.
  • The catalytic activity of SHIP2 is not essential for its inhibitory effect on preadipocyte proliferation via PDGFR pathway modulation.
  • SHIP2 PDR/AAA promotes PDGFR degradation, offering a novel mechanism impacting adipose tissue regulation.

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