Akt suppresses DLK for maintaining self-renewal of mouse embryonic stem cells

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Title:	Akt suppresses DLK for maintaining self-renewal of mouse embryonic stem cells
Authors:	馬念涵;Chen, Yi-Rong;Schuyler, Scott C.;Lu, Jean;Lin, Chia Hui;Hsiao, Michael;Hsu, Shu Ching;Wang, Chia-Hui;Ma, Nianhan;Wu, Hong Jin;Lu, Frank Leigh;Wu, Cheng Chung
Contributors:	生醫理工學院生醫科學與工程學系
Keywords:	Amino Acid Sequence;Animals;Cell Differentiation;Cell Line;Chromones;Homeodomain Proteins;Humans;MAP Kinase Kinase Kinases;Mice;Molecular Sequence Data;Morpholines;Mouse Embryonic Stem Cells;Mutagenesis, Site-Directed;Nanog Homeobox Protein;Octamer Transcription Factor-3;Phosphatidylinositol 3-Kinases;Phosphoinositide-3 Kinase Inhibitors;Phosphorylation;Proto-Oncogene Proteins c-akt;Rats;RNA Interference;RNA, Small Interfering;Sequence Alignment;Signal Transduction
Date:	2015-04-15
Issue Date:	2026-04-23 11:14:59 (UTC+8)
Publisher:	Landes Bioscience;Informa UK Limited
Abstract:	摘要： Mouse embryonic stem cells (ES cells) can proliferate indefinitely. To identify potential signals involved in suppression of self-renewal, we previously screened a kinase/phosphatase expression library in ES cells, and observed that inhibition of Dual Leucine zipper-bearing Kinase (DLK) increased relative cell numbers. DLK protein was detected in both the pluripotent and differentiated states of mouse ES cells while DLK kinase activity increased upon differentiation. Overexpression of DLK in mouse ES cells displayed reductions in relative cell/colony numbers and Nanog expression, suggesting a suppressive role of DLK in self-renewal. By examining protein sequences of DLK, we identified 2 putative Akt phosphorylation sites at S584 and T659. Blocking PI3K/Akt signaling with LY-294002 enhanced DLK kinase activity dramatically. We found that Akt interacts with and phosphorylates DLK. Mutations of DLK amino acid residues at putative Akt phosphorylation sites (S584A, T659A, or S584A and T659A) diminished the level of DLK phosphorylation. While the mutated DLKs (S584A, T659A, or S584A and T659A) were expressed, a further reduction in cell/colony numbers and Nanog expression appeared in mouse ES cells. In addition, these mutant DLKs (S584A, T659A, or S584A and T659A) exhibited more robust kinase activity and cell death compared to wild type DLK or green fluorescence (GFP) controls. In summary, our results show that DLK functions to suppress self-renewal of mouse ES cells and is restrained by Akt phosphorylation. 出版者： Informa UK Limited 出版日期： 2015-04-18 出處： Cell Cycle, 2015-04, Vol.14, p.1207-1217 資源來源： Taylor & Francis Journals Auto-Holdings Collection 識別號： ISSN: 1538-4101 識別號： EISSN: 1551-4005 識別號： DOI: 10.6084/m9.figshare.1405681.v2 識別號： DOI: 10.1080/15384101.2015.1014144 識別號： DOI: 10.6084/m9.figshare.1405681 識別號： DOI: 10.6084/m9.figshare.1405681.v3 識別號： DOI: 10.6084/m9.figshare.1405681.v1 識別號： DOI: 10.6084/m9.figshare.1405681.v4
Appears in Collections:	[Department of Biomedical Sciences and Engineering ] journal & Dissertation

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