Zap70 functions to maintain stemness of mouse embryonic stem cells by negatively regulating Jak1/Stat3/c-Myc signaling.
Zeta-chain-associated protein kinase-70 (Zap70), a Syk family tyrosine kinase, has been reported to be present exclusively in normal T-cells, natural killer cells, and B cells, serving as a pivotal regulator of antigen-mediated receptor signaling and development. In this study, we report that Zap70 is expressed in undifferentiated mouse embryonic stem cells (mESCs) and may critically regulate self-renewal and pluripotency in mESCs. We found that Zap70 knocked-down mESCs (Zap70KD) show sustained self-renewal and defective differentiation. In addition, we present evidence that the sustained self-renewal in Zap70KD is associated with enhanced Jak/Stat3 signaling and c-Myc induction. These altered signaling appears to result from upregulated leukemia inhibitory factor receptor and downregulated src homology region 2 domain containing phosphatase 1 (SHP-1) phosphatase activity. On the basis of these results, we propose that in undifferentiated mESCs, Zap70 plays important roles in modulating the balance between self-renewal capacity and pluripotent differentiation ability as a key regulator of the Jak/Stat3/c-Myc signaling pathway.
Cha
Young
Y
Department of Biomedical Science, College of Life Science, CHA University, Pochon-si Gyeonggi-do, Korea.
Moon
Bo-hyun
BH
Lee
Mi-ok
MO
Ahn
Hee-jin
HJ
Lee
Hye-jin
HJ
Lee
Kyung-ah
KA
Fornace
Albert J
AJ
Kim
Kwang-soo
KS
Cha
Hyuk-jin
HJ
Park
Kyung-soon
KS
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000201:enzymology*; D018507:Gene Expression Regulation, Developmental; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D039904:Pluripotent Stem Cells / Q000201:enzymology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D053606:Receptors, OSM-LIF / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013724:Teratoma / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000378:metabolism*
C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse