Hypoxia and hypoxia/reoxygenation activate Src family tyrosine kinases and p21(ras) in cultured rat cardiac myocytes

We previously reported that both hypoxia and hypoxia followed by reoxygenation (hypoxia/reoxygenation) rapidly and sequentially activate mitogen-activated protein kinase kinase kinase (MAPKKK) activity of Raf-1. This was followed by the sequential activation of MAP kinase kinase (MAPKK), MAP kinases (p42(mapk) and p44(mapk)), and S6 kinase (p90(rsk)). In this study, we demonstrated that both hypoxia and hypoxia/reoxygenation caused rapid activation of Src family tyrosine kinases, p60(c-src) and p59(c-fyn), which are upstream mediators of MAP kinase activation. This was followed by the activation of p21(ras). Because Src family tyrosine kinases are known to be cell-surface-associated kinases and upstream regulators of p21(ras), these results strongly suggested that activation of Src family tyrosine kinases plays a key role in triggering intracellular signaling cascades in cardiac myocytes in response to hypoxia and hypoxia/reoxygenation. (C) 1996 Academic Press, Inc.