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SAPK/Jun amino-terminal kinases (JNK) are MAPK family members that are activated by a variety of environmental stresses, pro-inflammatory cytokines, growth factors, and GPCR agonists. Small GTPases of the Rho family deliver stress signals to this cascade (Rac, Rho, cdc42). As is the case with the other MAPKs, the membrane proximal kinase is a MAPKKK, typically MEKK1–4, or a mixed lineage kinase (MLK) that phosphorylates and activates MKK4 (SEK) or MKK7, the SAPK/JNK kinases.
JNK is required for apoptosis, inflammation, cytokine production, and metabolism. Environmental stresses (ionizing radiation, heat, oxidative stress, and DNA damage), as well as inflammatory cytokines and growth factors, activate the JNK module, and signaling to the JNK module frequently involves the Rho family GTPases Cdc42 and Rac. These receptors or receptor-independent stress-induced membrane changes then transmit signals to adaptor proteins, which can activate kinases in the MAP4K and, occasionally, MAP3K tiers of the JNK cascade on their own. Following that, activated MAP3Ks transmit signals to MAPKK kinases, primarily MKK4 and MKK7. As with the other MAPKKs, the major JNK kinases (MKK4, MKK7) are activated by phosphorylation of the characteristic Ser-Xaa-Ala-Xaa-Ser/Thr motif (Ser 198, Thr 202 in MKK7) and are then capable of transmitting the signal to the JNK level. JNKs, like other MAPKs, translocate into the nucleus shortly after activation, where they typically physically associate with and activate their targets, transcription factors such as c-Jun, ATF, and Elk1.
The c-Jun N-terminal kinases (JNKs), also known as stress-activated protein kinases (SAPKs), were initially discovered using extracts from UV-stimulated HeLa cells in a c-Jun binding assay. MKK4 and MKK7 activate JNKs by concurrently phosphorylating a threonine and a tyrosine residue within a conserved T-P-Y motif in the kinase domain's activation loop. While jnk1 and jnk2 are widely expressed, jnk3 is primarily expressed in the brain, heart, and testis.
In general, the JNK pathway is a "death" signaling pathway. It regulates the cell's response to potentially harmful extracellular stimuli such as inflammatory cytokines, UV or gamma irradiation, and so on. Under these adverse conditions, cells may develop DNA mutations or damage. If the DNA damage cannot be repaired immediately, the cell must be programmed to die (a process known as apoptosis) in order to avoid these undesirable mutations or damage. The JNK signaling pathway is an example of a death pathway that regulates cell death.