BMP4 Signaling Acts via dual-specificity phosphatase 9 to control ERK activity in mouse embryonic stem cells.
Extrinsic BMP and LIF signaling collaboratively maintain mouse embryonic stem cell (ESC) pluripotency, whereas appropriate ERK activity is essential for ESC fate commitment. However, how the extrinsic signals restrain appropriate ERK activity remains elusive. Here, we show that, whereas LIF sustains relatively high ERK activity, BMP4 can steadily attenuate ERK activity by upregulating ERK-specific dual-specificity phosphatase 9 (DUSP9). This upregulation requires Smad1/5 and Smad4 and specifically occurs to DUSP9, but not other DUSPs, and only in ESCs. Through DUSP9-mediated inhibition of ERK activity, BMP signaling reinforces the self-renewal status of mouse ESCs together with LIF. Upon LIF withdrawal, ESCs spontaneously undergo neural differentiation, during which process DUSP9 can partially mediate BMP inhibition on neural commitment. Collectively, our findings identify DUSP9 as a critical mediator of BMP signaling to control appropriate ERK activity critical for ESC fate determination.
The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Zhongwei
Z
Li
Teng
T
Fei
Jianping
J
Zhang
Gaoyang
G
Zhu
Lu
L
Wang
Danyu
D
Lu
Xiaochun
X
Chi
Yan
Y
Teng
Ning
N
Hou
Xiao
X
Yang
Hongquan
H
Zhang
Jing-Dong J
JD
Han
Ye-Guang
YG
Chen
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000502:physiology*; D004789:Enzyme Activation; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D051785:Smad Proteins; D019950:Mitogen-Activated Protein Kinase 1; D054637:Dual-Specificity Phosphatases; C484491:Dusp9 protein, mouse