Hematopoietic Stem Cell Activity Is Regulated by Pten Phosphorylation Through a Niche-Dependent Mechanism.
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. Stem Cells 2016;34:2130-2144.
Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China.|Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA.
Jing
J
Li
Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China.|Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA.
Jun
J
Zhang
Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA.
Minghui
M
Tang
Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA.
Junping
J
Xin
Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China.
Yan
Y
Xu
Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA.
Andrew
A
Volk
Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China.
Caiqin
C
Hao
Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China.
Chenglong
C
Hu
Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China.
Jiewen
J
Sun
Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA.
Wei
W
Wei
Department of Public Health Sciences, Loyola University Chicago, Chicago, Illinois, USA.
Quichan
Q
Cao
Department of Biology, Loyola University Chicago, Chicago, Illinois, USA.|Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA.|Department of Molecular and Cellular Physiology, Loyola University Chicago, Chicago, Illinois, USA.
Peter
P
Breslin
Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA.|Department of Pathology, Loyola University Medical Center, Maywood, Illinois, USA.
Jiwang
J
Zhang
D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003260:Contact Inhibition; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D055153:Stem Cell Niche; D013997:Time Factors; D014161:Transduction, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D019000:Phosphotyrosine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase
Hematopoietic stem cells; Niche; Phosphorylation; Pten