Proteína quinase activada por mitóxeno: Diferenzas entre revisións

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Since the discovery of Ste5 in yeast, scientists were on the hunt to discover similar non-enzymatic scaffolding pathway elements in mammals. There are indeed a number of proteins involved in ERK signaling, that can bind to multiple elements of the pathway: [[MAP2K1IP1|MP1]] binds both MKK1/2 and ERK1/2, [[KSR1]] and [[KSR2]] can bind B-Raf or c-Raf, MKK1/2 and ERK1/2. Analogous proteins were also discovered for the JNK pathway: the [[MAPK8IP1|JIP1]]/[[MAPK8IP2|JIP2]] and the [[MAPK8IP3|JIP3]]/[[MAPK8IP4|JIP4]] families of proteins were all shown to bind MLKs, MKK7 and any JNK kinase. Unfortunately, unlike the yeast Ste5, the mechanisms by which they regulate MAPK activation are considerably less understood. While Ste5 actually forms a ternary complex with Ste7 and Fus3 to promote phosphorylation of the latter, known mammalian scaffold proteins appear to work by very different mechanisms. For example, KSR1 and KSR2 are actually MAP3 kinases and related to the Raf proteins.<ref name="pmid22292131">{{cite journal | vauthors = McKay MM, Freeman AK, Morrison DK | title = Complexity in KSR function revealed by Raf inhibitor and KSR structure studies | journal = Small GTPases | volume = 2 | issue = 5 | pages = 276–281 | date = Sep 2011 | pmid = 22292131 | pmc = 3265819 | doi = 10.4161/sgtp.2.5.17740 }}</ref> Although KSRs alone display negligible MAP3 kinase activity, KSR proteins can still participate in the activation of Raf kinases by forming side-to-side heterodimers with them, providing an allosteric pair to turn on each enzymes.<ref name="pmid21441910">{{cite journal | vauthors = Brennan DF, Dar AC, Hertz NT, Chao WC, Burlingame AL, Shokat KM, Barford D | title = A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK | journal = Nature | volume = 472 | issue = 7343 | pages = 366–9 | date = Apr 2011 | pmid = 21441910 | doi = 10.1038/nature09860 }}</ref> JIPs on the other hand, are apparently transport proteins, responsible for enrichment of MAPK signaling components in certain compartments of polarized cells.<ref name="pmid18081006">{{cite journal | vauthors = Koushika SP | title = "JIP"ing along the axon: the complex roles of JIPs in axonal transport | journal = BioEssays | volume = 30 | issue = 1 | pages = 10–4 | date = Jan 2008 | pmid = 18081006 | doi = 10.1002/bies.20695 }}</ref> In this context, JNK-dependent phosphorylation of JIP1 (and possibly JIP2) provides a signal for JIPs to release the JIP-bound and inactive upstream pathway components, thus driving a strong local positive feedback loop.<ref name="pmid12756254">{{cite journal | vauthors = Nihalani D, Wong HN, Holzman LB | title = Recruitment of JNK to JIP1 and JNK-dependent JIP1 phosphorylation regulates JNK module dynamics and activation | journal = The Journal of Biological Chemistry | volume = 278 | issue = 31 | pages = 28694–702 | date = Aug 2003 | pmid = 12756254 | doi = 10.1074/jbc.M304212200 }}</ref> This sophisticated mechanism couples [[kinesin|kinesin-dependent transport]] to local JNK activation, not only in mammals, but also in the fruitfly ''[[Drosophila melanogaster]]''.<ref name="pmid17658258">{{cite journal | vauthors = Horiuchi D, Collins CA, Bhat P, Barkus RV, Diantonio A, Saxton WM | title = Control of a kinesin-cargo linkage mechanism by JNK pathway kinases | journal = Current Biology | volume = 17 | issue = 15 | pages = 1313–7 | date = Aug 2007 | pmid = 17658258 | pmc = 2041807 | doi = 10.1016/j.cub.2007.06.062 }}</ref>▼

== Como dianas terapéuticas ==▼