Mechanisms of Endothelin-Induced Mitogenesis and Activation of Stress Response Protein Kinases

Abstract

The study of signal transduction mechanisms activated by the endothelin (ET) family of vasoactive peptides is in its infancy compared to the study of growth factor activated pathways. The most proximal mechanisms activated by ETs are well known-activation of phospholipase Cβ, and subsequently protein kinase C, and activation of plasma membrane Ca2+ channels. What is only starting to become clear is how these proximal signaling pathways, initially thought to be strikingly different from the proximal mechanisms activated by growth factors, share many similarities and both culminate in the activation of the same protein serine/threonine kinase cascade that has dominated the research on growth factor signaling over the past several years. This cascade, the c-Raf-1/ERK (for extracellularsignal regulated kinase, also known as MAP or mitogen-activated protein kinase) cascade) is critical to the mitogenic response to growth factors. To understand ET-induced mitogenesis it is critical to understand how G-protein-coupled receptors activate this kinase cascade since it appears that this cascade transduces signals from cell surface receptors to the nucleus, thus altering the transcription of genes which lead to the mitogenic response. In this chapter I will first explore the role of the ETs as growth factors, and then will focus on the c-Raf-1/ERK cascade, the mechanisms of its activation by ET, including putative roles of nonreceptor tyrosine kinases, and its role in the mitogenic response. I will also discuss possible roles for other pathways in the mitogenic response to ETs, including phosphoinositide-3 Kinases.