Catalytically inactive SHIP2 inhibits proliferation by attenuating pdgf signaling in 3T3-L1 preadipocytes
✍ Scribed by Yulia Artemenko; AnneMarie Gagnon; Alexander Sorisky
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 396 KB
- Volume
- 218
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
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 PI3K/PI(3,4,5)P3/Akt and Shc/Ras/ERK1/2. 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‐L1 preadipocytes. Surprisingly, SHIP2 PDR/AAA inhibited proliferation more potently than wild‐type SHIP2. After three days of proliferation, phospho‐Akt, phospho‐ERK1/2, 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. J. Cell. Physiol. 218: 228–236, 2009. © 2008 Wiley‐Liss, Inc.