JNK and p38. While MAP kinases are serine/threonine-specific, they are activated by combined phosphorylation on serine/threonine and tyrosine residues. Activity of MAP kinases is restricted by a number of protein phosphatases, which remove the phosphate groups that are added to specific serine or threonine residues of the kinase and are required to maintain the kinase in an active conformation. Tyrosine-specific protein kinases Tyrosine-specific protein kinases ( and ) phosphorylate tyrosine amino acid residues, and like serine/threonine-specific kinases are used in signal transduction. They act primarily as growth factor receptors and in downstream signaling from growth factors. Some examples include: Platelet-derived growth factor receptor (PDGFR) Epidermal growth factor receptor (EGFR) Insulin receptor and insulin-like growth factor 1 receptor (IGF1R) Stem cell factor (SCF) receptor (also called c-kit, see the article on gastrointestinal stromal tumor). Receptor tyrosine kinases These kinases consist of extracellular domains, a transmembrane spanning alpha helix, and an intracellular tyrosine kinase domain protruding into the cytoplasm. They play important roles in regulating cell division, cellular differentiation, and morphogenesis. More than 50 receptor tyrosine kinases are known in mammals. Structure The extracellular domains serve as the ligand-binding part of the molecule, often inducing the domains to form homo- or heterodimers. The transmembrane element is a single α helix. The intracellular or cytoplasmic Protein kinase domain is responsible for the (highly conserved) kinase activity, as well as several regulatory functions. Regulation Ligand binding causes two reactions: Dimerization of two monomeric receptor kinases or stabilization of a loose dimer. Many ligands of receptor tyrosine kinases are multivalent. Some tyrosine receptor kinases (e.g., the platelet-derived growth factor receptor) can form heterodimers with other similar but not identical kinases of the same subfamily, allowing a highly varied response to the extracellular signal. Trans-autophosphorylation (phosphorylation by the other kinase in the dimer) of the kinase. Autophosphorylation stabilizes the active conformation of the kinase domain. When several amino acids suitable for phosphorylation are present in the kinase domain (e.g., the insulin-like growth factor receptor), the activity of the kinase can increase with the number of phosphorylated amino acids; in this case, the first phosphorylation switches the kinase from "off" to "standby". Signal transduction The active tyrosine kinase phosphorylates specific target proteins, which are often enzymes themselves. An important target is the ras protein signal-transduction chain. Receptor-associated tyrosine kinases Tyrosine kinases recruited to a receptor following hormone binding are receptor-associated tyrosine kinases and are involved in a