Hematopoietic Stem Cell Activity is Regulated by Pten Phosphorylation through a Niche-Dependent Mechanism Journal Article

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Authors: Li, J; Zhang, J; Tang, M.; Xin, J.; Xu, Y; Volk, A; Hao, C.; Hu, C; Sun, J; Wei, W.; Cao, Q; Breslin, P
Article Title: Hematopoietic Stem Cell Activity is Regulated by Pten Phosphorylation through a Niche-Dependent Mechanism
Abstract: The phosphorylated form of Pten (p-Pten) is highly expressed in >70% of acute myeloid leukemia (AML) samples. However, the role of p-Pten in normal and abnormal hematopoiesis has not been studied. We found that Pten protein levels are comparable among long-term (LT) hematopoietic stem cells (HSCs), short-term (ST) HSCs and multipotent progenitors (MPPs); however the levels of p-Pten are elevated during the HSC-to-MPP transition. To study whether p-Pten is involved in regulating self-renewal and differentiation in HSCs, we compared the effects of over-expression of p-Pten and non-phosphorylated Pten (non-p-Pten) on the hematopoietic reconstitutive capacity (HRC) of HSCs. We found that over-expression of non-p-Pten enhances the LT-HRC of HSCs, whereas over-expression of p-Pten promotes myeloid differentiation and compromises the LT-HRC of HSCs. Such phosphorylation-regulated Pten functioning is mediated by repressing the cell:cell contact-induced activation of Fak/p38 signaling independent of Pten's lipid phosphatase activity because both p-Pten and non-p-Pten have comparable activity in repressing PI3K/Akt signaling. Our studies suggest that, in addition to repressing PI3K/Akt/mTor signaling, non-p-Pten maintains HSCs in bone marrow niches via a cell-contact inhibitory mechanism by inhibiting Fak/p38 signaling-mediated proliferation and differentiation. In contrast, p-Pten promotes the proliferation and differentiation of HSCs by enhancing the cell contact-dependent activation of Src/Fak/p38 signaling. This article is protected by copyright. All rights reserved.
Journal Title: Stem cells (Dayton, Ohio)
ISSN: 1549-4918; 1066-5099
Publisher: AlphaMed Press  
Date Published: 2016
Language: ENG
DOI/URL:

10.1002/stem.2382
Notes: LR: 20160421; CI: (c) 2016; JID: 9304532; OTO: NOTNLM; 2015/11/04 [received]; 2016/03/19 [revised]; 2016/03/26 [accepted]; aheadofprint