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84-538: ErbB protein family signaling is important for development. For example, ErbB-2 and ErbB-4 knockout mice die at midgestation leads to deficient cardiac function associated with a lack of myocardial ventricular trabeculation and display abnormal development of the peripheral nervous system. In ErbB-3 receptor mutant mice, they have less severe defects in the heart and thus are able to survive longer throughout embryogenesis. Lack of Schwann cell maturation leads to degeneration of motor and sensory neurons. Excessive ErbB signaling

168-586: A GTP-bound state. The RAS pathway can couple with the mitogen-activated protein kinase pathway or a number of other possible effectors. The PI3K/Akt pathway is dysregulated in many human tumors because of mutations altering proteins in the pathway. In relation to breast tumors, somatic activating mutations in Akt and the p110α subunit of the PI3K have been detected in 3–5% and 20–25% of primary breast tumors, respectively. Many breast tumors also have lower levels of PTEN, which

252-557: A low FISH test ratio in estrogen receptor positive breast cancers are less likely to respond to this drug. ErbB expression as also been linked to cutaneous Squamous Cell Carcinoma (cSCC) development, where the over-expression of these receptors has been found in cSCC tumors. Based on a study conducted by Cañueto et al. (2017), ErbB over-expression in tumors was linked to lymph node progression and metastasis stage progression in cSCC. Schwann cell Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann ) are

336-530: A negative feedback mechanism to set the correct strength of ERK1/2 activation. 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: 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

420-576: 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 kinases MK2 and MK3 ), ensuring the need for both in order to respond to stressful stimuli. ERK5 is part of a fairly well-separated pathway in mammals. Its sole specific upstream activator MKK5 is turned on in response to the MAP3 kinases MEKK2 and MEKK3 . The specificity of these interactions are provided by

504-532: A pro-myelinating to myelinating state. In this way, in Krox-20 double knock out mice, it has been recorded that hindbrain segmentation is affected as well as myelination of Schwann cell associated axons. Indeed, in these mice, the Schwann cells are not able to perform their myelination properly as they only wrap their cytoplasmic processes one and half turn around the axon and despite the fact that they still express

588-482: A retro-inverse D-motif peptide from JIP1, formerly known as XG-102) is also under clinical development for sensorineural hearing loss . p38 was 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 in autoimmune diseases . Many of these compounds were found to be hepatotoxic to various degree and tolerance to

672-432: A role in maintaining the structural integrity of both myelin formation and the axon with which it is associated. P0- mice developed behavioral deficits around 2 weeks of age when mice began to show signs of slight trembling. Gross incoordination also arose as the animals developed, while trembling became more severe and some older mice developed convulsing behaviors. Despite the array of impaired motor behavior, no paralysis

756-520: A signal for JIPs to release the JIP-bound and inactive upstream pathway components, thus driving a strong local positive feedback loop. This sophisticated mechanism couples kinesin-dependent transport to local JNK activation, not only in mammals, but also in the fruitfly Drosophila melanogaster . Since the ERK signaling pathway is involved in both physiological and pathological cell proliferation, it

840-441: A smaller ligand (such as Ras for c-Raf , GADD45 for MEKK4 or Cdc42 for MLK3 ). This commonly (but not always) happens at the cell membrane, where most of their activators are bound (note that small G-proteins are constitutively membrane-associated due to prenylation ). That step is followed by side-to-side homo- and heterodimerisation of their now accessible kinase domains. Recently determined complex structures reveal that

924-453: A variety of glial cells that keep peripheral nerve fibres (both myelinated and unmyelinated) alive. In myelinated axons, Schwann cells form the myelin sheath. The sheath is not continuous. Individual myelinating Schwann cells cover about 1 mm of an axon  – equating to about 1000 Schwann cells along a 1-m length of the axon. The gaps between adjacent Schwann cells are called nodes of Ranvier . 9-O-Acetyl GD3 ganglioside

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1008-656: Is a lipid phosphatase that dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate, thereby reversing the action of PI3K. EGFR has been found to be overexpressed in many cancers such as gliomas and non-small-cell lung carcinoma. Drugs such as panitumumab , cetuximab , gefitinib , erlotinib , afatinib , and lapatinib are used to inhibit it. Cetuximab is a chimeric human: murin immunoglobulin G1 mAb that binds EGFR with high affinity and promotes EGFR internalization. It has recently been shown that acquired resistance to cetuximab and gefitinib can be linked to hyperactivity of ErbB-3. This

1092-596: Is a major signalling route for the ErbB family, as is the PI3-K/AKT pathway , both of which lead to increased cell proliferation and inhibition of apoptosis. Genetic Ras mutations are infrequent in breast cancer but Ras may be pathologically activated in breast cancer by overexpression of ErbB receptors. Activation of the receptor tyrosine kinases generates a signaling cascade where the Ras GTPase proteins are activated to

1176-542: Is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens , osmotic stress , heat shock and proinflammatory cytokines . They regulate cell functions including proliferation , gene expression , differentiation , mitosis , cell survival, and apoptosis . MAP kinases are found in eukaryotes only, but they are fairly diverse and encountered in all animals, fungi and plants, and even in an array of unicellular eukaryotes. MAPKs belong to

1260-555: Is an acetylated glycolipid which is found in the cell membranes of many types of vertebrate cells. During peripheral nerve regeneration , 9-O-acetyl GD3 is expressed by Schwann cells. The vertebrate nervous system relies on the myelin sheath for insulation and as a method of decreasing membrane capacitance in the axon. The action potential jumps from node to node, in a process called saltatory conduction , which can increase conduction velocity up to 10 times, without an increase in axonal diameter. In this sense, Schwann cells are

1344-439: Is associated with the development of a wide variety of types of solid tumor . ErbB-1 and ErbB-2 are found in many human cancers , and their excessive signaling may be critical factors in the development and malignancy of these tumors . The ErbB protein family consists of 4 members v-ErbBs are homologous to EGFR, but lack sequences within the ligand binding ectodomain. All four ErbB receptor family members are nearly same in

1428-595: Is conducted by specialized enzymes of the STE protein kinase group. In this way protein dynamics can induce a conformational change in the structure of the protein via long-range allostery . In the case of classical MAP kinases, the activation loop contains a characteristic TxY (threonine-x-tyrosine) motif (TEY in mammalian ERK1 and ERK2 , TDY in ERK5 , TPY in JNKs , TGY in p38 kinases ) that needs to be phosphorylated on both

1512-409: Is inactivated in mice, satellite glia and Schwann cell precursors fail to develop, though neurons are generated normally without issue. In the absence of SOX10, neural crest cells survive and are free to generate neurons, but glial specification is blocked. SOX10 might influence early glial precursors to respond to neuregulin 1 (see below). Neuregulin 1 (NRG1) acts in a number of ways to both promote

1596-658: Is linked to an acquired overexpression of c-MET , which phosphorylates ErbB-3, which in turn activates the AKT pathway . Panitumumab is a human mAb with high EGFR affinity that blocks ligand-binding to induce EGFR internalization. Panitumumab efficacy has been tested in a variety of advanced cancer patients, including renal carcinomas and metastatic colorectal cancer in clinical trials. ErbB2 overexpression can occur in breast, ovarian, bladder, non-small-cell lung carcinoma, as well as several other tumor types. Trastuzumab or Herceptin inhibits downstream signal cascades by selectively binding to

1680-581: Is made up of 4 subdomains, L1, CR1, L2, and CR2, where "L" signifies a leucine -rich repeat domain and "CR" a cysteine -rich region, and these CR domains contain disulfide modules in their structure as 8 disulfide modules in CR1 domain, whereas 7 modules in CR2 domain. These subdomains are shown in blue (L1), green (CR1), yellow (L2), and red (CR2) in the figure below. These subdomains are also referred to as domains I-IV, respectively. The intracellular/cytoplasmic region of

1764-606: Is natural that ERK1/2 inhibitors would represent a desirable class of antineoplastic agents. Indeed, many of the proto-oncogenic "driver" mutations are tied to ERK1/2 signaling, such as constitutively active (mutant) receptor tyrosine kinases , Ras or Raf proteins. Although no MKK1/2 or ERK1/2 inhibitors were developed for clinical use, kinase inhibitors that also inhibit Raf kinases (e.g. Sorafenib ) are successful antineoplastic agents against various types of cancer. MEK inhibitor cobimetinib has been investigated in pre-clinical lung cancer models in combination with inhibition of

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1848-449: Is not a generic, but a highly specialized function. Most MAPKs have a number of shared characteristics, such as the activation dependent on two phosphorylation events, 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

1932-449: Is required for neural crest cells to migrate past the site of dorsal root ganglia to find the ventral regions of sympathetic gangliogenesis. It is also an essential axon-derived survival factor and a mitogen for Schwann cell precursors. It is found in the dorsal root ganglion and motor neurons at the point in time that Schwann cell precursors begin to populate spinal nerves and therefore influences Schwann cell survival. In embryonic nerves,

2016-683: The PI3K pathway , where the two drugs lead to a synergistic response. JNK kinases are implicated in the development of insulin resistance in obese individuals as well as neurotransmitter excitotoxicity after 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. 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,

2100-445: The choanoflagellate Monosiga brevicollis ) closely related to the origins of multicellular animals. 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 of Giardia lamblia revealed the presence of two MAPK genes, one of them similar to

2184-570: The cyclin-dependent kinases (CDKs), where substrates are recognized by the cyclin subunit, 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

2268-406: The effector recognition signal from FLS2 ⇨ MEKK1 ⇨ MKK4 or MKK5 ⇨ MPK3 and MPK6 ⇨ WRKY22 or WRKY29. However the work of Mészáros et al. 2006 and Suarez-Rodriguez et al. 2007 give other orders for this pathway and it is possible that these are parallel pathways operating simultaneously. They are also involved in morphogenesis , since MPK4 mutants display severe dwarfism . Members of

2352-403: The growth cones . Schwann cells are essential for the maintenance of healthy axons. They produce a variety of factors, including neurotrophins , and also transfer essential molecules across to axons. SOX10 is a transcription factor active during embryonic development and abundant evidence indicates that it is essential for the generation of glial lineages from trunk crest cells. When SOX10

2436-460: The myelin sheath. The Schwann cell promoter is present in the downstream region of the human dystrophin gene that gives shortened transcript that are again synthesized in a tissue-specific manner. During the development of the PNS, the regulatory mechanisms of myelination are controlled by feedforward interaction of specific genes, influencing transcriptional cascades and shaping the morphology of

2520-519: The neurilemma . Only a small volume of residual cytoplasm allows communication between the inner and outer layers. This is seen histologically as the Schmidt-Lantermann incisure . Schwann cells are known for their roles in supporting nerve regeneration . Nerves in the PNS consist of many axons myelinated by Schwann cells. If damage occurs to a nerve, the Schwann cells aid in digestion of its axons ( phagocytosis ). Following this process,

2604-502: The sporulation pathway (Smk1). 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 of Arabidopsis thaliana are key mediators of responses to osmotic shock , oxidative stress , response to cold and involved in anti-pathogen responses. Asai et al. 2002's model of MAPK mediated immunity passes

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2688-429: The threonine and the tyrosine residues in order to lock the kinase domain in a catalytically competent conformation. In vivo and in vitro , phosphorylation of tyrosine oftentimes precedes phosphorylation of threonine, although phosphorylation of either residue can occur in the absence of the other. This tandem activation loop phosphorylation (that was proposed to be either distributive or processive, dependent on

2772-517: The CMGC (CDK/MAPK/GSK3/CLK) kinase group. The closest relatives of MAPKs are the cyclin-dependent kinases (CDKs). 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

2856-464: The ErbB family proteins, using the pdb files 1NQL (ErbB-1), 1S78 (ErbB-2), 1M6B (ErbB-3) and 2AHX (ErbB-4): The four members of the ErbB protein family are capable of forming homodimers , heterodimers , and possibly higher-order oligomers upon activation by a subset of potential growth factor ligands . There are 11 growth factors that activate ErbB receptors. The ability ('+') or inability ('-') of each growth factor to activate each of

2940-421: The ErbB receptor consists mainly of three subdomains: A juxtamembrane with approximately 40 residues, a kinase domain containing approximately 260 residues and a C-terminal domain of 220-350 amino acid residues that become activated via phosphorylation of its tyrosine residues that mediates interactions of other ErbB proteins and downstream signaling molecules. The figure below shows the tridimensional structure of

3024-411: The ErbB receptors is shown in the table below: The dimerization occurs after ligand bind to the extracellular domain of the ErbB monomers and monomer-monomer interaction establishes activating the activation loop in a kinase domain, that activates the further process of transphosphorylation of the specific tyrosine kinases in the kinase domain of ErbB's intracellular part. It is a complex process due to

3108-535: The Fus3 MAPK is responsible for cell cycle arrest and mating in response to pheromone stimulation. The pheromone alpha-factor is sensed by a seven transmembrane receptor . The recruitment and activation of Fus3 pathway components are strictly dependent on heterotrimeric G-protein activation. The mating MAPK pathway consist of three tiers (Ste11-Ste7-Fus3), but the MAP2 and MAP3 kinases are shared with another pathway,

3192-657: The JNK pathway: the JIP1 / JIP2 and the JIP3 /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

3276-573: 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

3360-669: 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 ( MKK3 and MKK6 ). Due to these interlocks, there are very few if any stimuli that can elicit JNK activation without simultaneously activating p38 or reversed. Both JNK and p38 signaling pathways are responsive to stress stimuli, such as cytokines , ultraviolet irradiation , heat shock , and osmotic shock , and are involved in adaptation to stress , apoptosis or cell differentiation . JNKs have

3444-470: 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. However, none of these groups can be directly equated to

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3528-613: The PNS's analogues of the central nervous system 's oligodendrocytes . However, unlike oligodendrocytes, each myelinating Schwann cell provides insulation to only one axon (see image). This arrangement permits saltatory conduction of action potentials with repropagation at the nodes of Ranvier. In this way, myelination greatly increases speed of conduction and saves energy. Nonmyelinating Schwann cells are involved in maintenance of axons and are crucial for neuronal survival. Some group around smaller axons ( External image here ) and form Remak bundles . Myelinating Schwann cells begin to form

3612-545: The Raf proteins. 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. JIPs on the other hand, are apparently transport proteins, responsible for enrichment of MAPK signaling components in certain compartments of polarized cells. In this context, JNK-dependent phosphorylation of JIP1 (and possibly JIP2) provides

3696-558: The Schwann cells can guide regeneration by forming a type of tunnel that leads toward the target neurons. This tunnel is known as band of Büngner , a guidance track for the regenerating axons, which behaves like an endoneural tube. The stump of the damaged axon is able to sprout, and those sprouts that grow through the Schwann-cell "tunnel" do so at the rate around 1 mm/day in good conditions. The rate of regeneration decreases with time. Successful axons can, therefore, reconnect with

3780-545: 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. The ERK1/2 pathway of mammals is probably the best-characterized MAPK system. The most important upstream activators of this pathway are the Raf proteins ( A-Raf , B-Raf or c-Raf ), the key mediators of response to growth factors ( EGF , FGF , PDGF , etc.); but other MAP3Ks such as c-Mos and Tpl2/Cot can also play

3864-413: The activation of the whole range of downstream signaling pathways like PLCγ, ERK 1/2, p38 MAPK , PI3-K/Akt and more with the cell. When not bound to a ligand, the extracellular regions of ErbB1, ErbB3, and ErbB4 are found in a tethered conformation in which a 10-amino-acid-long dimerization arm is unable to mediate monomer-monomer interactions. In contrast, in ligand-bound ErbB-1 and unliganded ErbB-2,

3948-495: The actual MAP kinase. In contrast to the relatively simple, phosphorylation-dependent activation mechanism of MAPKs and MAP2Ks , MAP3Ks have stunningly complex regulation. Many of the better-known MAP3Ks , such as c-Raf , MEKK4 or MLK3 require 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

4032-426: The already-well-known mammalian MAPKs (ERKs, p38s, etc.), the other one showing similarities to the mammalian ERK7 protein. The situation is similar in the multicellular amoeba Dictyostelium discoideum , where the ddERK1 protein appears to be a classical MAPK, while ddERK2 more closely resembles our ERK7 and ERK3/4 proteins. Atypical MAPKs can also be found in higher plants, although they are poorly known. Similar to

4116-440: The cell membrane (where many MAP3Ks are activated) to the nucleus (where only MAPKs may enter) or to many other subcellular targets. In comparison to the three-tiered classical MAPK pathways, some atypical MAP kinases appear to have a more ancient, two-tiered system. ERK3 (MAPK6) and ERK4 (MAPK4) were recently shown to be directly phosphorylated and thus activated by PAK kinases (related to other MAP3 kinases). In contrast to

4200-524: The cellular environment) is performed by members of the Ste7 protein kinase family, also known as MAP2 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

4284-482: The classical MAP kinases, these atypical MAPKs require only a single residue in their activation loops to be phosphorylated. The details of NLK and ERK7 (MAPK15) activation remain unknown. Inactivation of MAPKs is performed by a number of phosphatases . A very conserved family of dedicated phosphatases is the so-called MAP kinase phosphatases (MKPs), a subgroup of dual-specificity phosphatases (DUSPs). As their name implies, these enzymes are capable of hydrolyzing

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4368-596: The clusters of classical MAPKs found in opisthokonts (fungi and animals). In the latter, the major subgroups of classical MAPKs form the ERK/Fus3-like branch (that is further sub-divided in metazoans into 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). 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

4452-437: The cytoplasmic domain of ErbB-1, that may become phosphorylated and in some cases de-phosphorylated (e.g., Tyr 992) upon receptor dimerization. Although a number of potential phosphorylation sites exist, upon dimerization only one or much more rarely two of these sites are phosphorylated at any one time. Phosphorylated tyrosine residues act as binding sites for intracellular signal activators such as Ras. The Ras-Raf-MAPK pathway

4536-457: The dedicated MAP3 kinases involved in activation are Ssk2 and SSk22. The system in S. cerevisiae is 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

4620-465: The dimerization arm becomes untethered and exposed at the receptor surface, making monomer-monomer interactions and dimerisation possible. The consequence of ectodomain dimerization is the positioning of two cytoplasmic domains such that transphosphorylation of specific tyrosine , serine , and threonine amino acids can occur within the cytoplasmic domain of each ErbB. At least 10 specific tyrosines, 7 serines, and 2 threonines have been identified within

4704-417: The dimers are formed in an orientation that leaves both their substrate-binding regions free. 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

4788-527: The domain specificity and nature of the members of ErbB family. Notably, the ErbB1 and ErbB4 are the two most studied and intact among the family of ErbB proteins, Which forms functional intracellular tyrosine kinases. ErbB2 has no known binding ligand and absent of an active kinase domain in ErbB3 make this duo preferable to form heterodimers & share each other's active domains to activate transphosphorylation of

4872-757: The early myelin marker, late myelin gene products are absent. In addition, recent studies have also proven the importance of this transcription factor in maintaining the myelination phenotype (and requires the co-expression of Sox 10) as its inactivation leads to dedifferentiation of the Schwann cells. Charcot–Marie–Tooth disease (CMT), Guillain–Barré syndrome (GBS, acute inflammatory demyelinating polyradiculopathy type), schwannomatosis , and chronic inflammatory demyelinating polyneuropathy (CIDP), leprosy , and Zika Virus are all neuropathies involving Schwann cells. A number of experimental studies since 2001 have implanted Schwann cells in an attempt to induce remyelination in multiple sclerosis -afflicted patients. In

4956-583: The embryonic lethality of ERK5 inactivation due to cardiac abnormalities underlines its central role in mammalian vasculogenesis . It is notable, that conditional knockout of ERK5 in adult animals is also lethal, due to the widespread disruption of endothelial barriers . Mutations in the upstream components of the ERK5 pathway (the CCM complex) are thought to underlie cerebral cavernous malformations in humans. MAPK pathways of fungi are also well studied. In yeast,

5040-581: The entire MAPK family (ERK3, ERK4, ERK7). In vertebrates, due to the twin whole genome duplications after the cephalochordate/vertebrate split, there are several paralogs in every group. Thus ERK1 and ERK2 both correspond to the Drosophila kinase rolled , JNK1, JNK2 and JNK3 are all orthologous to the gene basket in Drosophila . Although among the p38 group, p38 alpha and beta are clearly paralogous pairs, and so are p38 gamma and delta in vertebrates,

5124-468: The extracellular domain of ErbB-2 receptors to inhibit it. This leads to decreased proliferation of tumor cells. Trastuzumab targets tumor cells and causes apoptosis through the immune system by promoting antibody-dependent cellular cytotoxicity. Two thirds of women respond to trastuzumab. Although herceptin works well in most breast cancer cases, it has not been yet elucidated as to why some HER2-positive breast cancers don't respond well. Research suggests that

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5208-625: The features required by other MAPKs for substrate binding. These are usually referred to as "atypical" MAPKs. It is yet unclear if the atypical MAPKs form a single group as opposed to the classical ones. The mammalian MAPK family of kinases includes three subfamilies: Generally, ERKs are activated by growth factors and mitogens , whereas cellular stresses and inflammatory cytokines activate JNKs and p38s. 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

5292-586: The filamentous growth pathway to be activated only in the absence of Ste5 recruitment. Fungi also have a pathway reminiscent of mammalian JNK/p38 signaling. This is the Hog1 pathway: activated by high osmolarity (in Saccharomyces cerevisiae ) or a number of other abiotic stresses (in Schizosaccharomyces pombe ). The MAP2 kinase of this pathway is called Pbs2 (related to mammalian MKK3/4/6/7),

5376-411: The formation and ensure the survival of immature Schwann cells. During embryonic development, NRG1 inhibits the formation of neurons from neural crest cells, instead contributing to neural crest cells being led down a path to gliogenesis. NRG1 signaling is not, however, required for glial differentiation from the neural crest. NRG1 plays important roles in the development of neural crest derivatives. It

5460-552: The muscles or organs they previously controlled with the help of Schwann cells, but specificity is not maintained and errors are frequent, especially when long distances are involved. Because of their ability to impact regeneration of axons, Schwann cells have been connected to preferential motor reinnervation , as well. If Schwann cells are prevented from associating with axons, the axons die. Regenerating axons will not reach any target unless Schwann cells are there to support them and guide them. They have been shown to be in advance of

5544-410: The myelin sheath in mammals during fetal development and work by spiraling around the axon, sometimes with as many as 100 revolutions. A well-developed Schwann cell is shaped like a rolled-up sheet of paper, with layers of myelin between each coil. The inner layers of the wrapping, which are predominantly membrane material, form the myelin sheath, while the outermost layer of nucleated cytoplasm forms

5628-668: The myelinated nerve fibers. Schwann cells are involved in many important aspects of peripheral nerve biology – the conduction of nervous impulses along axons , nerve development and regeneration , trophic support for neurons , production of the nerve extracellular matrix, modulation of neuromuscular synaptic activity, and presentation of antigens to T-lymphocytes . Charcot–Marie–Tooth disease , Guillain–Barré syndrome (acute inflammatory demyelinating polyradiculopathy type), schwannomatosis , chronic inflammatory demyelinating polyneuropathy , and leprosy are all neuropathies involving Schwann cells. Schwann cells are

5712-409: The myelination process is Krox-20. It is a general zinc-finger transcription factor and is expressed in the rhombomeres 3 and 5. Krox-20 is considered one of the master regulators of PNS myelination and is important in driving transcription of specific structural proteins in the myelin. It has been shown to control a set of genes responsible for interfering with this feature in the axon changing it from

5796-407: 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 . Thus the role of mammalian ERK1/2 kinases as regulators of cell proliferation

5880-469: The past two decades, many studies have demonstrated positive results and potential for Schwann cell transplantation as a therapy for spinal cord injury, both in aiding regrowth and myelination of damaged CNS axons. Schwann cell transplants in combination with other therapies such as Chondroitinase ABC have also been shown to be effective in functional recovery from spinal cord injury. MAPK A mitogen-activated protein kinase ( MAPK or MAP kinase )

5964-426: The phosphate from both phosphotyrosine and the phosphothreonine residues. Since removal of either phosphate groups will greatly reduce MAPK activity, essentially abolishing signaling, some tyrosine phosphatases are also involved in inactivating MAP kinases (e.g. the phosphatases HePTP , STEP and PTPRR in mammals). As mentioned above, MAPKs typically form multi-tiered pathways, receiving input several levels above

6048-542: The phosphorylation site by 10–50 amino acids. 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 their N-termini that are absolutely required for MAP2K-MAPK interaction and MAPK activation. Similarly, both dual-specificity MAP kinase phosphatases and MAP-specific tyrosine phosphatases bind to MAP kinases through

6132-550: The phosphorylation site. 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

6216-484: The principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells , olfactory ensheathing cells , enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle . The two types of Schwann cells are myelinating and nonmyelinating . Myelinating Schwann cells wrap around axons of motor and sensory neurons to form

6300-538: The same docking site. D-motifs can even be found in certain MAPK pathway regulators and scaffolds (e.g. in the mammalian JIP proteins). 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

6384-546: The same role. All these enzymes phosphorylate and thus activate the MKK1 and/or MKK2 kinases, that are highly specific activators for ERK1 and ERK2 . The latter phosphorylate a number of substrates important for cell proliferation , cell cycle progression , cell division and differentiation ( RSK kinases , Elk-1 transcription factor , etc.) In contrast to the relatively well-insulated ERK1/2 pathway , mammalian p38 and JNK kinases have most of their activators shared at

6468-471: The sheath. P0 has been shown to be essential for the formation of compact myelin, as P0 null mutant (P0-) mice showed severely aberrant peripheral myelination. Although myelination of large caliber axons was initiated in P0- mice, the resulting myelin layers were very thin and poorly compacted. Unexpectedly, P0- mice also showed degeneration of both axons and their surround myelin sheaths, suggesting that P0 plays

6552-608: The situation in mammals, most aspects of atypical MAPKs are uncharacterized due to the lack of research focus on this area. As typical for the CMGC kinase group, the catalytic site of MAP kinases has a very loose consensus sequence for substrates . Like all their relatives, they only require the target serine / threonine amino acids to be followed by a small amino acid, preferably proline ("proline-directed kinases"). But as SP/TP sites are extremely common in all proteins, additional substrate-recognition mechanisms have evolved to ensure signaling fidelity. Unlike their closest relatives,

6636-429: The structure having single-chain of modular glycoproteins. This structure is made up of an extracellular region or ectodomain or ligand binding region that contains approximately 620 amino acids , a single transmembrane -spanning region containing approximately 23 residues, and an intracellular cytoplasmic tyrosine kinase domain containing up to approximately 540 residues. The extracellular region of each family member

6720-554: The timing of the base split is less clear, given that many metazoans already possess multiple p38 homologs (there are three p38-type kinases in Drosophila , Mpk2 ( p38a ), p38b and p38c ). 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 in protostomes , together with its upstream pathway components (MEKK2/3, MKK5), although they are clearly present in cnidarians , sponges and even in certain unicellular organisms (e.g.

6804-417: The transmembrane III isoform likely is the primary variant of NRG1 responsible for survival signals. In mice that lack the transmembrane III isoform, Schwann cell precursors are eventually eliminated from spinal nerves. Myelin protein zero (P0) is a cell-adhesion molecule belonging to the immunoglobulin superfamily and is the major component of peripheral myelin, constituting over 50% of the total protein in

6888-429: The tyrosine kinases. The specific tyrosine molecules mainly trans or auto-phosphorylated are at the site Y992, Y1045, Y1068, Y1148, Y1173 in the tail region of the ErbB monomer. For the activation of kinase domain in the ErbB dimer, asymmetric kinase domain dimer of the two monomers is required with the intact asymmetric (N-C lobe) interface at the site of adjoining monomers. Activation of the tyrosine kinase domain leads to

6972-726: The unique architecture of MKK5 and MEKK2/3, both containing N-terminal PB1 domains, enabling direct heterodimerisation with each other. The PB1 domain of MKK5 also contributes to the ERK5-MKK5 interaction: it provides a special interface (in addition to the D-motif found in MKK5) through which MKK5 can specifically recognize its substrate ERK5. Although the molecular-level details are poorly known, MEKK2 and MEKK3 respond to certain developmental cues to direct endothel formation and cardiac morphogenesis . While also implicated in brain development,

7056-475: Was observed in these animals. P0 is also an important gene expressed early within the Schwann cell lineage, expressed in Schwann cell precursors after differentiating from migrating neural crest cells within the developing embryo. Several important transcription factors are also expressed and involved at various stages in development changing the features on the Schwann cells from an immature to mature state. One indispensable transcription factor expressed during

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