Phosphorylation stabilizes Nanog by promoting its interaction with Pin1.
Embryonic stem cells (ESCs) can undergo unlimited self-renewal and retain the pluripotency to differentiate into all cell types in the body, thus holding great promise as a renewable source of cells for human therapy. The mechanisms that maintain self-renewal of ESCs remain unclear. Here we show that Nanog, a transcription factor crucial for the self-renewal of ESCs, is phosphorylated at multiple Ser/Thr-Pro motifs. This phosphorylation promotes the interaction between Nanog and the prolyl isomerase Pin1, leading to Nanog stabilization by suppressing its ubiquitination. Inhibition of Pin1 activity or disruption of Pin1-Nanog interaction in ESCs suppresses their capability to self-renew and to form teratomas in immunodeficient mice. Therefore, in addition to the stringent transcriptional regulation of Nanog, the expression level of Nanog is also modulated by posttranslational mechanisms.
Moretto-Zita
Matteo
M
Section of Molecular Biology and Cell and Developmental Biology, Division of Biological Sciences, University of California, La Jolla, CA 92093-0322, USA.
Jin
Hua
H
Shen
Zhouxin
Z
Zhao
Tongbiao
T
Briggs
Steven P
SP
Xu
Yang
Y
D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D000071317:Nanog Homeobox Protein; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010618:Phenanthrolines / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D013724:Teratoma / Q000473:pathology / Q000517:prevention & control; D054875:Ubiquitination
D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D000071317:Nanog Homeobox Protein; D010618:Phenanthrolines; C552250:diethyl-1,3,6,8-tetrahydro-1,3,6,8-tetraoxobenzo(lmn)(3,8)phenanthroline-2,7-diacetate; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse