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Mitogen-activated protein kinase

(Redirected fromMAPK)
See also:extracellular signal-regulated kinases

Amitogen-activated protein kinase(MAPKorMAP kinase) is a type ofserine/threonine-specific protein kinasesinvolved in directing cellular responses to a diverse array of stimuli, such asmitogens,osmotic stress,heat shockandproinflammatory cytokines.They regulate cell functions includingproliferation,gene expression,differentiation,mitosis,cell survival, andapoptosis.[1]

Mitogen-activated protein kinase
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MAP kinases are found ineukaryotesonly, but they are fairly diverse and encountered in all animals, fungi and plants, and even in an array of unicellular eukaryotes.[citation needed]

MAPKs belong to the CMGC (CDK/MAPK/GSK3/CLK) kinase group. The closest relatives of MAPKs are thecyclin-dependent kinases(CDKs).[2]

Discovery

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The first mitogen-activated protein kinase to be discovered was ERK1 (MAPK3) in mammals. Since ERK1 and its close relative ERK2 (MAPK1) are both involved in growth factor signaling, the family was termed "mitogen-activated". With the discovery of other members, even from distant organisms (e.g. plants), it has become increasingly clear that the name is a misnomer, since most MAPKs are actually involved in the response to potentially harmful, abiotic stress stimuli (hyperosmosis, oxidative stress, DNA damage, low osmolarity, infection, etc.). Because plants cannot "flee" from stress, terrestrial plants have the highest number of MAPK genes per organism ever found[citation needed].Thus the role of mammalian ERK1/2 kinases as regulators of cell proliferation is not a generic, but a highly specialized function.

Types

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Most MAPKs have a number of shared characteristics, such as the activation dependent on twophosphorylationevents, a three-tiered pathway architecture and similar substrate recognition sites. These are the "classical" MAP kinases. But there are also some ancient outliers from the group as sketched above, that do not have dual phosphorylation sites, only form two-tiered pathways, and lack the features required by other MAPKs for substrate binding. These are usually referred to as "atypical" MAPKs.[3]It is yet unclear if the atypical MAPKs form a single group as opposed to the classical ones.[clarification needed]

The mammalian MAPK family of kinases includes three subfamilies:

  1. Extracellular signal-regulated kinases(ERKs)
  2. c-Jun N-terminal kinases(JNKs)
  3. p38 mitogen-activated protein kinases(p38s)[4][5]

Generally, ERKs are activated bygrowth factorsandmitogens,whereascellular stressesandinflammatory cytokinesactivate JNKs and p38s.[4]

Activation

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X-ray structure of the ERK2 MAP kinase in its active form. Phosphorylated residues are displayed in red. Rendering based on pdb entry 2ERK.

Mitogen-activated protein kinases are catalytically inactive in their base form. In order to become active, they require (potentially multiple) phosphorylation events in their activation loops. This is conducted by specialized enzymes of the STE protein kinase group. In this wayprotein dynamicscan induce aconformational changein the structure of the protein via long-rangeallostery.[citation needed]

In the case of classical MAP kinases, theactivation loopcontains a characteristic TxY (threonine-x-tyrosine) motif (TEY in mammalianERK1andERK2,TDY inERK5,TPY inJNKs,TGY inp38 kinases) that needs to be phosphorylated on both thethreonineand thetyrosineresidues in order to lock the kinase domain in a catalytically competent conformation.In vivoandin vitro,phosphorylation of tyrosine oftentimes precedes phosphorylation of threonine, although phosphorylation of either residue can occur in the absence of the other.[citation needed]

This tandemactivation loopphosphorylation (that was proposed to be either distributive or processive, dependent on the cellular environment) is performed by members of the Ste7 protein kinase family, also known asMAP2 kinases.MAP2 kinases in turn, are also activated by phosphorylation, by a number of different upstream serine-threonine kinases (MAP3 kinases). Because MAP2 kinases display very little activity on substrates other than their cognate MAPK, classical MAPK pathways form multi-tiered, but relatively linear pathways. These pathways can effectively convey stimuli from the cell membrane (where many MAP3Ks are activated) to the nucleus (where only MAPKs may enter) or to many other subcellular targets.[citation needed]

In comparison to the three-tiered classical MAPK pathways, some atypical MAP kinases appear to have a more ancient, two-tiered system.ERK3(MAPK6) andERK4(MAPK4) were recently shown to be directly phosphorylated and thus activated byPAK kinases(related to other MAP3 kinases).[6]In contrast to the classical MAP kinases, these atypical MAPKs require only a single residue in their activation loops to be phosphorylated. The details ofNLKandERK7(MAPK15) activation remain unknown.[citation needed]

Inactivation of MAPKs is performed by a number ofphosphatases.A very conserved family of dedicated phosphatases is the so-calledMAP kinase phosphatases(MKPs), a subgroup ofdual-specificity phosphatases(DUSPs).[7]As their name implies, these enzymes are capable of hydrolyzing the phosphate from both phosphotyrosine and the phosphothreonine residues. Since removal of either phosphate groups will greatly reduce MAPK activity, essentially abolishing signaling, sometyrosine phosphatasesare also involved in inactivating MAP kinases (e.g. the phosphatasesHePTP,STEPandPTPRRin mammals).[citation needed]

Signaling cascades

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Example for the inner workings of a MAP3 kinase: the activation cycle of mammalian Raf proteins (greatly simplified overview)[8][9]

As mentioned above, MAPKs typically form multi-tiered pathways, receiving input several levels above the actual MAP kinase. In contrast to the relatively simple, phosphorylation-dependent activation mechanism of MAPKs andMAP2Ks,MAP3Ks have stunningly complex regulation. Many of the better-knownMAP3Ks,such asc-Raf,MEKK4orMLK3require multiple steps for their activation. These are typically allosterically-controlled enzymes, tightly locked into an inactive state by multiple mechanisms. The first step en route to their activation consists of relieving their autoinhibition by a smaller ligand (such asRasforc-Raf,GADD45forMEKK4[10]orCdc42for MLK3[11]). This commonly (but not always) happens at the cell membrane, where most of their activators are bound (note thatsmall G-proteinsare constitutively membrane-associated due toprenylation). That step is followed by side-to-side homo- and heterodimerisation of their now accessible kinase domains. Recently determined complex structures reveal that the dimers are formed in an orientation that leaves both their substrate-binding regions free.[12]Importantly, this dimerisation event also forces the MAP3 kinase domains to adopt a partially active conformation. Full activity is only achieved once these dimers transphosphorylate each other on their activation loops. The latter step can also be achieved or aided by auxiliary protein kinases (MAP4 kinases, members of the Ste20 family). Once a MAP3 kinase is fully active, it may phosphorylate its substrate MAP2 kinases, which in turn will phosphorylate their MAP kinase substrates.[citation needed]

In animals

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A simplified overview of MAPK pathways in mammals, organised into three main signaling modules (ERK1/2, JNK/p38 and ERK5)

TheERK1/2pathway of mammals is probably the best-characterized MAPK system. The most important upstream activators of this pathway are the Raf proteins (A-Raf,B-Raforc-Raf), the key mediators of response to growth factors (EGF,FGF,PDGF,etc.); but other MAP3Ks such as c-Mos andTpl2/Cotcan also play the same role. All these enzymes phosphorylate and thus activate theMKK1and/orMKK2kinases, that are highly specific activators forERK1andERK2.The latter phosphorylate a number of substrates important forcell proliferation,cell cycle progression,cell divisionanddifferentiation(RSK kinases,Elk-1transcription factor,etc.)[citation needed]

In contrast to the relatively well-insulatedERK1/2 pathway,mammalianp38andJNK kinaseshave most of their activators shared at the MAP3K level (MEKK1,MEKK4,ASK1,TAK1,MLK3,TAOK1,etc.). In addition, some MAP2K enzymes may activate both p38 and JNK (MKK4), while others are more specific for either JNK (MKK7) or p38 (MKK3andMKK6). Due to these interlocks, there are very few if any stimuli that can elicit JNK activation without simultaneously activating p38 or reversed.[13]Both JNK and p38 signaling pathways are responsive to stress stimuli, such ascytokines,ultraviolet irradiation,heat shock,andosmotic shock,and are involved inadaptation to stress,apoptosisorcell differentiation.JNKs have a number of dedicated substrates that only they can phosphorylate (c-Jun,NFAT4,etc.), while p38s also have some unique targets (e.g. the MAPKAP kinasesMK2andMK3), ensuring the need for both in order to respond to stressful stimuli.[citation needed]

ERK5is part of a fairly well-separated pathway in mammals. Its sole specific upstream activatorMKK5is turned on in response to the MAP3 kinasesMEKK2andMEKK3.The specificity of these interactions are provided by the unique architecture of MKK5 and MEKK2/3, both containing N-terminal PB1 domains, enabling direct heterodimerisation with each other.[14]The PB1 domain of MKK5 also contributes to the ERK5-MKK5 interaction: it provides a special interface (in addition to theD-motiffound in MKK5) through which MKK5 can specifically recognize its substrate ERK5.[15]Although the molecular-level details are poorly known, MEKK2 and MEKK3 respond to certain developmental cues to directendothelformation andcardiac morphogenesis.While also implicated in brain development, the embryonic lethality of ERK5 inactivation due tocardiac abnormalitiesunderlines its central role in mammalianvasculogenesis.[16]It is notable, thatconditional knockoutof ERK5 in adult animals is also lethal, due to the widespread disruption ofendothelial barriers.[17]Mutations in the upstream components of the ERK5 pathway (the CCM complex) are thought to underliecerebral cavernous malformationsin humans.[citation needed]

In fungi

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Overview of MAPK pathways in yeast. Non-canonical components of the five known modules (mating, filamentation, hyperosmosis, cell wall integrity, sporulation pathways) are colored in blue.

MAPK pathways of fungi are also well studied. In yeast, the Fus3 MAPK is responsible for cell cycle arrest andmatingin response to pheromone stimulation. The pheromone Alpha -factor is sensed by aseven transmembrane receptor.The recruitment and activation of Fus3 pathway components are strictly dependent onheterotrimeric G-proteinactivation. The mating MAPK pathway consist of three tiers (Ste11-Ste7-Fus3), but the MAP2 and MAP3 kinases are shared with another pathway, the Kss1 or filamentous growth pathway. While Fus3 and Kss1 are closely related ERK-type kinases, yeast cells can still activate them separately, with the help of a scaffold protein Ste5 that is selectively recruited by the G-proteins of the mating pathway. The trick is that Ste5 can associate with and "unlock" Fus3 for Ste7 as a substrate in a tertiary complex, while it does not do the same for Kss1, leaving the filamentous growth pathway to be activated only in the absence of Ste5 recruitment.[18]

Fungi also have a pathway reminiscent of mammalian JNK/p38 signaling. This is the Hog1 pathway: activated by high osmolarity (inSaccharomyces cerevisiae) or a number of other abiotic stresses (inSchizosaccharomyces pombe). The MAP2 kinase of this pathway is called Pbs2 (related to mammalian MKK3/4/6/7), the dedicated MAP3 kinases involved in activation are Ssk2 and SSk22. The system inS. cerevisiaeis activated by a sophisticated osmosensing module consisting of the Sho1 and Sln1 proteins, but it is yet unclear how other stimuli can elicit activation of Hog1. Yeast also displays a number of other MAPK pathways without close homologs in animals, such as the cell wall integrity pathway (Mpk1/Slt2) or thesporulationpathway (Smk1).[19]

In plants

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Despite the high number of MAPK genes, MAPK pathways of higher plants were studied less than animal or fungal ones. Although their signaling appears very complex, the MPK3, MPK4 and MPK6 kinases ofArabidopsis thalianaare key mediators of responses toosmotic shock,oxidative stress,response to cold and involved in anti-pathogen responses.[20][21][22]Asaiet al.2002's model of MAPK mediated immunity passes theeffectorrecognition signal fromFLS2⇨MEKK1⇨MKK4orMKK5⇨ MPK3 and MPK6 ⇨ WRKY22 or WRKY29.[22]However the work of Mészároset al.2006 and Suarez-Rodriguezet al.2007 give other orders for this pathway and it is possible that these are parallel pathways operating simultaneously.[22]They are also involved inmorphogenesis,since MPK4 mutants display severedwarfism.[23]

Evolutionary relationships

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The evolutionary origins of human mitogen-activated protein kinases (MAPKs)[15][24]

Members of the MAPK family can be found in every eukaryotic organism examined so far. In particular, both classical and atypical MAP kinases can be traced back to the root of the radiation of major eukaryotic groups. Terrestrial plants contain four groups of classical MAPKs (MAPK-A, MAPK-B, MAPK-C and MAPK-D) that are involved in response to myriads of abiotic stresses.[25]However, none of these groups can be directly equated to the clusters of classical MAPKs found inopisthokonts(fungi and animals). In the latter, the major subgroups of classical MAPKs form the ERK/Fus3-like branch (that is further sub-divided inmetazoansinto ERK1/2 and ERK5 subgroups), and the p38/Hog1-like kinases (that has also split into the p38 and the JNK subgroups in multicellular animals).[26]In addition, there are several MAPKs in both fungi and animals, whose origins are less clear, either due to high divergence (e.g. NLK), or due to possibly being an early offshoot to the entire MAPK family (ERK3, ERK4, ERK7). In vertebrates, due to the twin whole genome duplications after the cephalochordate/vertebrate split,[27]there are several paralogs in every group. Thus ERK1 and ERK2 both correspond to theDrosophilakinaserolled,JNK1, JNK2 and JNK3 are all orthologous to the genebasketinDrosophila.Although among the p38 group, p38 Alpha and beta are clearly paralogous pairs, and so are p38 gamma and delta in vertebrates, the timing of the base split is less clear, given that many metazoans already possess multiple p38 homologs (there are three p38-type kinases inDrosophila,Mpk2(p38a),p38bandp38c). The single ERK5 protein appears to fill a very specialized role (essential for vascular development in vertebrates) wherever it is present. This lineage has been deleted inprotostomes,together with its upstream pathway components (MEKK2/3, MKK5), although they are clearly present incnidarians,spongesand even in certain unicellular organisms (e.g. thechoanoflagellateMonosiga brevicollis) closely related to the origins of multicellular animals.[28]

The split between classical and some atypical MAP kinases happened quite early. This is suggested not just by the high divergence between extant genes, but also recent discoveries of atypical MAPKs in primitive, basal eukaryotes. The genome sequencing ofGiardia lambliarevealed the presence of two MAPK genes, one of them similar to the already-well-known mammalian MAPKs (ERKs, p38s, etc.), the other one showing similarities to the mammalian ERK7 protein.[29]The situation is similar in the multicellular amoebaDictyostelium discoideum,where the ddERK1 protein appears to be a classical MAPK, while ddERK2 more closely resembles our ERK7 and ERK3/4 proteins.[30]Atypical MAPKs can also be found in higher plants, although they are poorly known. Similar to the situation in mammals, most aspects of atypical MAPKs are uncharacterized due to the lack of research focus on this area.[citation needed]

Substrate and partner recognition

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The overview of the D-motif dependent MAPK interactions and substrate recognition.[31]All cited examples refer to the interactions of the mammalian ERK2 protein.

As typical for the CMGC kinase group, the catalytic site of MAP kinases has a very loose consensus sequence forsubstrates.Like all their relatives, they only require the targetserine/threonineamino acids to be followed by a small amino acid, preferablyproline( "proline-directed kinases" ). But as SP/TP sites are extremely common in all proteins, additional substrate-recognition mechanisms have evolved to ensure signaling fidelity.[31]Unlike their closest relatives, thecyclin-dependent kinases(CDKs), where substrates are recognized by thecyclinsubunit, MAPKs associate with their substrates via auxiliary binding regions on their kinase domains. The most important such region consists of the hydrophobic docking groove and the negatively charged CD-region. Together they recognize the so-called MAPK docking or D-motifs (also called kinase interaction motif / KIM). D-motifs essentially consist of one or two positively charged amino acids, followed by alternating hydrophobic residues (mostly leucines), typically upstream of the phosphorylation site by 10–50 amino acids.[32]Many of the known MAPK substrates contain such D-motifs that can not only bind to, but also provide specific recognition by certain MAPKs. D-motifs are not restricted to substrates: MAP2 kinases also contain such motifs on theirN-terminithat are absolutely required for MAP2K-MAPK interaction and MAPK activation.[33]Similarly, both dual-specificity MAP kinase phosphatases and MAP-specific tyrosine phosphatases bind to MAP kinases through the same docking site.[34][35]D-motifs can even be found in certain MAPK pathway regulators and scaffolds (e.g. in the mammalian JIP proteins).[citation needed]

Other, less well characterised substrate-binding sites also exist. One such site (the DEF site) is formed by the activation loop (when in the active conformation) and the MAP kinase-specific insert below it. This site can accommodate peptides with an FxFP consensus sequence, typically downstream of the phosphorylation site.[36]Note that the latter site can only be found in proteins that need to selectively recognize the active MAP kinases, thus they are almost exclusively found in substrates. Different motifs may cooperate with each other, as in the Elk family of transcription factors, that possess both a D-motif and an FxFP motif. The presence of an FxFP motif in the KSR1 scaffold protein also serves to make it an ERK1/2 substrate, providing a negative feedback mechanism to set the correct strength of ERK1/2 activation.[citation needed]

Scaffold proteins

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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:MP1binds both MKK1/2 and ERK1/2,KSR1andKSR2can bind B-Raf or c-Raf, MKK1/2 and ERK1/2. Analogous proteins were also discovered for the JNK pathway: theJIP1/JIP2and theJIP3/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.[37]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.[38]JIPs on the other hand, are apparently transport proteins, responsible for enrichment of MAPK signaling components in certain compartments of polarized cells.[39]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.[40]This sophisticated mechanism coupleskinesin-dependent transportto local JNK activation, not only in mammals, but also in the fruitflyDrosophila melanogaster.[41]

As therapeutic targets

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Since theERK signaling pathwayis involved in both physiological and pathological cell proliferation, it is natural that ERK1/2 inhibitors would represent a desirable class ofantineoplasticagents. Indeed, many of the proto-oncogenic "driver" mutations are tied to ERK1/2 signaling, such as constitutively active (mutant)receptor tyrosine kinases,RasorRafproteins. Although no MKK1/2 or ERK1/2 inhibitors were developed for clinical use, kinase inhibitors that also inhibitRaf kinases(e.g.Sorafenib) are successful antineoplastic agents against various types of cancer.[42][43]MEK inhibitorcobimetinibhas been investigated in pre-clinical lung cancer models in combination with inhibition of thePI3K pathway,where the two drugs lead to a synergistic response.[44][45]

JNK kinasesare implicated in the development ofinsulin resistancein obese individuals[46]as well as neurotransmitterexcitotoxicityafter ischaemic conditions. Inhibition of JNK1 ameliorates insulin resistance in certain animal models. Mice that were genetically engineered to lack a functional JNK3 gene - the major isoform in brain – display enhanced ischemic tolerance and stroke recovery.[47]Although small-molecule JNK inhibitors are under development, none of them proved to be effective in human tests yet. A peptide-based JNK inhibitor (AM-111, a retro-inverse D-motif peptide from JIP1, formerly known as XG-102) is also under clinical development forsensorineural hearing loss.[48]

p38was once believed to be a perfect target for anti-inflammatory drugs. Yet the failure of more than a dozen chemically different compounds in the clinical phase suggests that p38 kinases might be poor therapeutic targets inautoimmune diseases.Many of these compounds were found to behepatotoxicto various degree and tolerance to the anti-inflammatory effect developed within weeks.[49]An alternative approach is to evaluate the potential for targeting upstream MAPKs, such asASK1.[50]Studies in animal models of inflammatory arthritis have yielded promising results, and ASK1 has recently been found to be unique amongst the MAPKs in that it is inducible by inflammatory cytokines such asTNF-α.[50]

See also

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References

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