Open AccessHematopoietic Stem Cell Activity Is Regulated by Pten Phosphorylation Through a Niche‐Dependent Mechanism
Author(s) -
Li Jing,
Zhang Jun,
Tang Minghui,
Xin Junping,
Xu Yan,
Volk Andrew,
Hao Caiqin,
Hu Chenglong,
Sun Jiewen,
Wei Wei,
Cao Quichan,
Breslin Peter,
Zhang Jiwang
Publication year - 2016
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2382
Subject(s) - biology , stem cell , mechanism (biology) , microbiology and biotechnology , phosphorylation , niche , pten , haematopoiesis , stem cell niche , hematopoietic stem cell , cancer research , signal transduction , biochemistry , progenitor cell , pi3k/akt/mtor pathway , philosophy , epistemology
Abstract The phosphorylated form of Pten (p‐Pten) is highly expressed in >70% of acute myeloid leukemia 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 overexpression of p‐Pten and nonphosphorylated Pten (non‐p‐Pten) on the hematopoietic reconstitutive capacity (HRC) of HSCs. We found that overexpression of non‐p‐Pten enhances the LT‐HRC of HSCs, whereas overexpression 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. S tem C ells 2016;34:2130–2144