A conserved mechanism for control of human and mouse embryonic stem cell pluripotency and differentiation by shp2 tyrosine phosphatase.
Recent studies have suggested distinctive biological properties and signaling mechanisms between human and mouse embryonic stem cells (hESCs and mESCs). Herein we report that Shp2, a protein tyrosine phosphatase with two SH2 domains, has a conserved role in orchestration of intracellular signaling cascades resulting in initiation of differentiation in both hESCs and mESCs. Homozygous deletion of Shp2 in mESCs inhibited differentiation into all three germ layers, and siRNA-mediated knockdown of Shp2 expression in hESCs led to a similar phenotype of impaired differentiation. A small molecule inhibitor of Shp2 enzyme suppressed both hESC and mESC differentiation capacity. Shp2 modulates Erk, Stat3 and Smad pathways in ES cells and, in particular, Shp2 regulates BMP4-Smad pathway bi-directionally in mESCs and hESCs. These results reveal a common signaling mechanism shared by human and mouse ESCs via Shp2 modulation of overlapping and divergent pathways.
Wu
Dongmei
D
Programs in Signal Transduction, and Stem Cells and Regeneration, Burnham Institute for Medical Research, La Jolla, California, United States of America.
Pang
Yuhong
Y
Ke
Yuehai
Y
Yu
Jianxiu
J
He
Zhao
Z
Tautz
Lutz
L
Mustelin
Tomas
T
Ding
Sheng
S
Huang
Ziwei
Z
Feng
Gen-Sheng
GS
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000201:enzymology; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000201:enzymology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D034741:RNA, Small Interfering; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11