PMID- 27096933 OWN - NLM STAT- MEDLINE DCOM- 20171212 LR - 20220316 IS - 1549-4918 (Electronic) IS - 1066-5099 (Linking) VI - 34 IP - 8 DP - 2016 Aug TI - Hematopoietic Stem Cell Activity Is Regulated by Pten Phosphorylation Through a Niche-Dependent Mechanism. PG - 2130-44 LID - 10.1002/stem.2382 [doi] AB - 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. CI - (c) 2016 AlphaMed Press. FAU - Li, Jing AU - Li J AD - Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China. AD - Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA. FAU - Zhang, Jun AU - Zhang J AD - Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China. AD - Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA. FAU - Tang, Minghui AU - Tang M AD - Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA. FAU - Xin, Junping AU - Xin J AD - Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA. FAU - Xu, Yan AU - Xu Y AD - Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China. FAU - Volk, Andrew AU - Volk A AD - Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA. FAU - Hao, Caiqin AU - Hao C AD - Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China. FAU - Hu, Chenglong AU - Hu C AD - Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China. FAU - Sun, Jiewen AU - Sun J AD - Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China. FAU - Wei, Wei AU - Wei W AD - Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA. FAU - Cao, Quichan AU - Cao Q AD - Department of Public Health Sciences, Loyola University Chicago, Chicago, Illinois, USA. FAU - Breslin, Peter AU - Breslin P AD - Department of Biology, Loyola University Chicago, Chicago, Illinois, USA. AD - Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA. AD - Department of Molecular and Cellular Physiology, Loyola University Chicago, Chicago, Illinois, USA. FAU - Zhang, Jiwang AU - Zhang J AD - Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA. AD - Department of Pathology, Loyola University Medical Center, Maywood, Illinois, USA. LA - eng GR - R01 HL095896/HL/NHLBI NIH HHS/United States GR - R01 HL133560/HL/NHLBI NIH HHS/United States GR - R21 CA181970/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160519 PL - England TA - Stem Cells JT - Stem cells (Dayton, Ohio) JID - 9304532 RN - 21820-51-9 (Phosphotyrosine) RN - EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases) RN - EC 2.7.10.2 (src-Family Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) SB - IM MH - Animals MH - Cell Differentiation MH - Cell Line, Tumor MH - Cell Movement MH - Cell Proliferation MH - Contact Inhibition MH - Focal Adhesion Protein-Tyrosine Kinases/antagonists & inhibitors/metabolism MH - Hematopoietic Stem Cells/*metabolism MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Mice, Inbred C57BL MH - Myeloid Progenitor Cells/cytology/metabolism MH - Neoplasm Invasiveness MH - PTEN Phosphohydrolase/*metabolism MH - Phosphorylation MH - Phosphotyrosine/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - *Stem Cell Niche MH - Time Factors MH - Transduction, Genetic MH - p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism MH - src-Family Kinases/metabolism OTO - NOTNLM OT - Hematopoietic stem cells OT - Niche OT - Phosphorylation OT - Pten EDAT- 2016/04/21 06:00 MHDA- 2017/12/13 06:00 CRDT- 2016/04/21 06:00 PHST- 2015/11/04 00:00 [received] PHST- 2016/03/19 00:00 [revised] PHST- 2016/03/26 00:00 [accepted] PHST- 2016/04/21 06:00 [entrez] PHST- 2016/04/21 06:00 [pubmed] PHST- 2017/12/13 06:00 [medline] AID - 10.1002/stem.2382 [doi] PST - ppublish SO - Stem Cells. 2016 Aug;34(8):2130-44. doi: 10.1002/stem.2382. Epub 2016 May 19.