Catalytically inactive Ship2 inhibits proliferation by attenuating PDGF signaling in 3T3-L1 preadipocytes

Yulia Artemenko, Annemarie Gagnon, Alexander Sorisky

Research output: Contribution to journalArticle

Abstract

Inadequate proliferation and/or differentiation of preadipocytes may lead to adipose tissue dysfunction characterized by hypertrophied, insulin-resistant adipocytes. Platelet-derived growth factor (PDGF) may alter adipose tissue function by promoting proliferation of preadipocytes. Two principal signaling pathways that regulate proliferation are P13K/PI(3,4,5)P3/Akt and Shc/Ras/ERK 1/2. SH2 domain-containing inositol 5-phosphatase 2 (SHIP2) dephosphorylates PI(3,4,5)P3, and also binds to Shc. Our goal was to determine how SHIP2 affects these PDGF signaling routes. To assess the role of the 5-phosphatase domain, we expressed wild-type or catalytically inactive dominant-negative SHIP2 (P686A-D690A-R691A; PDR/AAA) in 3T3-LI preadipocytes. Surprisingly, SHIP2 PDR/AAA inhibited proliferation more potently than wild-type SHIP2. After three days of proliferation, phospho-Akt, phospho-ERK 1/2, and PDGF receptor (PDGFR) levels were reduced in PDR/AAA-expressing preadipocytes. SHIP2 PDR/AAA interference with PDGFR signaling was demonstrated using imatinib, an inhibitor of PDGFR tyrosine kinase. The anti-proliferative effect of imatinib observed in control preadipocytes was not significant in SHIP2 PDR/AAA-expressing preadipocytes, indicating a pre-existing impairment of PDGFR-dependent mitogenesis in these cells. The inhibition of PDGF-activated mitogenic pathways by SHIP2 PDR/AAA was consistent with a decrease in PDGFR phosphorylation caused by a drop in receptor levels in SHIP2 PDR/AAA-expressing cells. SHIP2 PDR/AAA promoted ubiquitination of the PDGFR and its degradation via the lysosomal pathway independently of the association between the E3 ubiquitin ligase c-Cbl and PDGFR. Overall, our findings indicate that SHIP2 PDR/AAA reduces preadipocyte proliferation by attenuating PDGFR signaling.

Original languageEnglish (US)
Pages (from-to)228-236
Number of pages9
JournalJournal of Cellular Physiology
Volume218
Issue number1
DOIs
StatePublished - Jan 2009
Externally publishedYes

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src Homology Domains
Platelet-Derived Growth Factor
Phosphoric Monoester Hydrolases
Inositol
Platelet-Derived Growth Factor Receptors
Adipose Tissue
Inositol Polyphosphate 5-Phosphatases
Tissue
Ubiquitin-Protein Ligases
Ubiquitination
Phosphorylation
Adipocytes
Insulin
Association reactions

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Catalytically inactive Ship2 inhibits proliferation by attenuating PDGF signaling in 3T3-L1 preadipocytes. / Artemenko, Yulia; Gagnon, Annemarie; Sorisky, Alexander.

In: Journal of Cellular Physiology, Vol. 218, No. 1, 01.2009, p. 228-236.

Research output: Contribution to journalArticle

Artemenko, Yulia ; Gagnon, Annemarie ; Sorisky, Alexander. / Catalytically inactive Ship2 inhibits proliferation by attenuating PDGF signaling in 3T3-L1 preadipocytes. In: Journal of Cellular Physiology. 2009 ; Vol. 218, No. 1. pp. 228-236.
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