-!- Phosphorylation of specific tyrosine and threonine residues in the activation loop of this enzyme by EC 2.7.12.2 is necessary for enzyme activation. -!- Once activated, the enzyme phosphorylates target substrates on serine or threonine residues followed by a proline. -!- A distinguishing feature of all MAPKs is the conserved sequence Thr- Xaa-Tyr (TXY). -!- Mitogen-activated protein kinase (MAPK) signal transduction pathways are among the most widespread mechanisms of cellular regulation. -!- Mammalian MAPK pathways can be recruited by a wide variety of stimuli including hormones (e.g. insulin and growth hormone), mitogens (e.g. epidermal growth factor and platelet-derived growth factor), vasoactive peptides (e.g. angiotensin-II and endothelin), inflammatory cytokines of the tumor necrosis factor (TNF) family and environmental stresses such as osmotic shock, ionizing radiation and ischemeic injury. -!- Formerly EC 2.7.1.37.