title: Differential effects on cell motility, embryonic stem cell self-renewal and senescence by diverse Src kinase family inhibitors.
abstract: The Src family of non-receptor tyrosine kinases (SFKs) has been shown to play an intricate role in embryonic stem (ES) cell maintenance. In the present study we have focused on the underlying molecular mechanisms responsible for the vastly different effects induced by various commonly used SFK inhibitors. We show that several diverse cell types, including fibroblasts completely lacking SFKs, cannot undergo mitosis in response to SU6656 and that this is caused by an unselective inhibition of Aurora kinases. In contrast, PP2 and PD173952 block motility immediately upon exposure and forces cells to grow in dense colonies. The subsequent halt in proliferation of fibroblast and epithelial cells in the center of the colonies approximately 24 h post-treatment appears to be caused by cell-to-cell contact inhibition rather than a direct effect of SFK kinase inhibition. Interestingly, in addition to generating more homogenous and dense ES cell cultures, without any diverse effect on proliferation, PP2 and PD173652 also promote ES cell self-renewal by reducing the small amount of spontaneous differentiation typically observed under standard ES cell culture conditions. These effects could not be mirrored by the use of Gleevec, a potent inhibitor of c-Abl and PDGFR kinases that are also inhibited by PP2.
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. christoffer.tamm@imbim.uu.se
authors.forename: Christoffer
authors.initials: C
authors.lastname: Tamm
authors.forename: Sara Pijuan
authors.initials: SP
authors.lastname: Galitó
authors.forename: Cecilia
authors.initials: C
authors.lastname: Annerén
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000235:genetics; D051575:Proto-Oncogene Proteins c-yes / Q000037:antagonists & inhibitors / Q000235:genetics; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: C412373:AG 1879; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C416927:SU 6656; D013449:Sulfonamides; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D051575:Proto-Oncogene Proteins c-yes; D016392:Proto-Oncogene Proteins pp60(c-src); C496639:Yes1 protein, mouse; D019061:src-Family Kinases