The Src family of tyrosine kinases is important for embryonic stem cell self-renewal.
cYes, a member of the Src family of non-receptor tyrosine kinases, is highly expressed in mouse and human embryonic stem (ES) cells. We demonstrate that cYes kinase activity is regulated by leukemia inhibitory factor (LIF) and serum and is down-regulated when cells differentiate. Moreover, selective chemical inhibition of Src family kinases decreases growth and expression of stem cell genes that mark the undifferentiated state, including Oct3/4, alkaline phosphatase, fibroblast growth factor 4, and Nanog. A synergistic effect on differentiation is observed when ES cells are cultured with an Src family inhibitor and low levels of retinoic acid. Src family kinase inhibition does not interfere with LIF-induced JAK/STAT3 (Janus-associated tyrosine kinases/signal transducer and activator of transcription 3) or p42/p44 MAPK (mitogen-activated protein kinase) phosphorylation. Together the results suggest that the activation of the Src family is important for maintaining mouse and human ES in an undifferentiated state and may represent a third, independent pathway, downstream of LIF in mouse ES cells.
Annerén
Cecilia
C
Howard Hughes Medical Institute and Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Cowan
Chad A
CA
Melton
Douglas A
DA
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D020935:MAP Kinase Signaling System; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D011506:Proteins / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D011506:Proteins; D034741:RNA, Small Interfering; D019061:src-Family Kinases