P38 mitogen-activated protein kinases

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mitogen-activated protein kinase 11
Identifiers
Symbol MAPK11
Alt. symbolsPRKM11
NCBI gene 5600
HGNC 6873
OMIM 602898
RefSeq NM_002751
UniProt Q15759
Other data
EC number 2.7.11.24
Locus Chr. 22 q13.33
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Structures Swiss-model
Domains InterPro
mitogen-activated protein kinase 12
Identifiers
Symbol MAPK12
Alt. symbolsSAPK3
NCBI gene 6300
HGNC 6874
OMIM 602399
RefSeq NM_002969
UniProt P53778
Other data
EC number 2.7.11.24
Locus Chr. 22 q13.3
Search for
Structures Swiss-model
Domains InterPro
mitogen-activated protein kinase 13
Identifiers
Symbol MAPK13
Alt. symbolsPRKM13
NCBI gene 5603
HGNC 6875
OMIM 602899
RefSeq NM_002754
UniProt O15264
Other data
EC number 2.7.11.24
Locus Chr. 6 p21
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Structures Swiss-model
Domains InterPro
mitogen-activated protein kinase 14
Identifiers
Symbol MAPK14
Alt. symbolsCSPB1, CSBP1, CSBP2
NCBI gene 1432
HGNC 6876
OMIM 600289
RefSeq NM_001315
UniProt Q16539
Other data
EC number 2.7.11.24
Locus Chr. 6 p21.3-21.2
Search for
Structures Swiss-model
Domains InterPro

p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation, apoptosis and autophagy. Persistent activation of the p38 MAPK pathway in muscle satellite cells (muscle stem cells) due to ageing, impairs muscle regeneration. [1] [2]

Contents

p38 MAP Kinase (MAPK), also called RK or CSBP (Cytokinin Specific Binding Protein), is the mammalian orthologue of the yeast Hog1p MAP kinase, [3] which participates in a signaling cascade controlling cellular responses to cytokines and stress.

Four p38 MAP kinases, p38-α (MAPK14), -β (MAPK11), -γ (MAPK12 / ERK6), and -δ (MAPK13 / SAPK4), have been identified. Similar to the SAPK/JNK pathway, p38 MAP kinase is activated by a variety of cellular stresses including osmotic shock, inflammatory cytokines, lipopolysaccharides (LPS), ultraviolet light, and growth factors.

MKK3 and SEK activate p38 MAP kinase by phosphorylation at Thr-180 and Tyr-182. Activated p38 MAP kinase has been shown to phosphorylate and activate MAPKAP kinase 2 and to phosphorylate the transcription factors ATF2, Mac, MEF2, and p53. [4] p38 also has been shown to phosphorylate post-transcriptional regulating factors like TTP, [5] and in fruit flies it plays a role in regulating the circadian clock. [6]

Clinical significance

Oxidative stress is the most powerfully specific stress activating p38 MAPK. [7] Abnormal activity (higher or lower than physiological) of p38 has been implicated in pathological stresses in several tissues, that include neuronal, [8] [9] [10] bone, [11] lung, [12] cardiac and skeletal muscle, [13] [14] red blood cells, [15] and fetal tissues. [16] The protein product of proto-oncogene RAS can increase activity of p38, and thereby cause excessively high activity of transcription factor NF-κB. This transcription factor is normally regulated from intracellular pathways that integrate signals from the surrounding tissue and the immune system. In turn these signals coordinate between cell survival and cell death. Dysregulated NF-κB activity can activate genes that cause cancer cell survival, and can also activate genes that facilitate cancer cell metastasis to other tissues. [17] P38 was also shown to correlate with outcome of glioblastoma - higher pathway activity is associated with low survival. [18]

Inhibitors

p38 inhibitors are being sought for possible therapeutic effect on autoimmune diseases and inflammatory processes, [19] e.g. pamapimod. [20] Some have started clinical trials, e.g. PH-797804 for COPD. [21] Other p38 inhibitors include BIRB 796, VX-702, SB239063, SB202190, SB203580, SCIO 469, and BMS 582949.

As of 2020, losmapimod, a p38 inhibitor, is being investigated for the treatment of facioscapulohumeral muscular dystrophy (FSHD) on the basis of p38 inhibition inhibiting the effects of DUX4. [22]

Related Research Articles

A mitogen-activated protein kinase is a type of protein kinase that is specific to the amino acids serine and threonine. MAPKs are 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.

Biological crosstalk refers to instances in which one or more components of one signal transduction pathway affects another. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction pathways, there are often shared components that can interact with either pathway. A more complex instance of crosstalk can be observed with transmembrane crosstalk between the extracellular matrix (ECM) and the cytoskeleton.

Mitogen Activated Protein (MAP) kinase kinase kinase is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but are mainly characterized by the MAP kinases they activate. MAPKKKs are stimulated by a large range of stimuli, primarily environmental and intracellular stressors. MAPKKK is responsible for various cell functions such as cell proliferation, cell differentiation, and apoptosis. The duration and intensity of signals determine which pathway ensues. Additionally, the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction. Lastly, because MAPKKK is involved in a series of several pathways, it has been used as a therapeutic target for cancer, amyloidosis, and neurodegenerative diseases. In humans, there are at least 19 genes which encode MAP kinase kinase kinases:

The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.

In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells. Many different stimuli, including growth factors, cytokines, virus infection, ligands for heterotrimeric G protein-coupled receptors, transforming agents, and carcinogens, activate the ERK pathway.

c-Jun N-terminal kinases Chemical compounds

c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock. They also play a role in T cell differentiation and the cellular apoptosis pathway. Activation occurs through a dual phosphorylation of threonine (Thr) and tyrosine (Tyr) residues within a Thr-Pro-Tyr motif located in kinase subdomain VIII. Activation is carried out by two MAP kinase kinases, MKK4 and MKK7, and JNK can be inactivated by Ser/Thr and Tyr protein phosphatases. It has been suggested that this signaling pathway contributes to inflammatory responses in mammals and insects.

<span class="mw-page-title-main">ASK1</span> Protein-coding gene in the species Homo sapiens

Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. ASK1 has been found to be involved in cancer, diabetes, rheumatoid arthritis, cardiovascular and neurodegenerative diseases.

<span class="mw-page-title-main">MAPK14</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.

<span class="mw-page-title-main">MAP3K7</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, is an enzyme that in humans is encoded by the MAP3K7 gene.

<span class="mw-page-title-main">ELK1</span> Protein-coding gene in humans

ETS Like-1 protein Elk-1 is a protein that in humans is encoded by the ELK1. Elk-1 functions as a transcription activator. It is classified as a ternary complex factor (TCF), a subclass of the ETS family, which is characterized by a common protein domain that regulates DNA binding to target sequences. Elk1 plays important roles in various contexts, including long-term memory formation, drug addiction, Alzheimer's disease, Down syndrome, breast cancer, and depression.

<span class="mw-page-title-main">MAPKAPK2</span> Protein-coding gene in the species Homo sapiens

MAP kinase-activated protein kinase 2 is an enzyme that in humans is encoded by the MAPKAPK2 gene.

<span class="mw-page-title-main">MAP2K6</span> Protein-coding gene in the species Homo sapiens

Dual specificity mitogen-activated protein kinase kinase 6 also known as MAP kinase kinase 6 or MAPK/ERK kinase 6 is an enzyme that in humans is encoded by the MAP2K6 gene, on chromosome 17.

<span class="mw-page-title-main">MAP2K3</span> Protein-coding gene in the species Homo sapiens

Dual specificity mitogen-activated protein kinase kinase 3 is an enzyme that in humans is encoded by the MAP2K3 gene.

<span class="mw-page-title-main">MAP3K4</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 4 is an enzyme that in humans is encoded by the MAP3K4 gene.

<span class="mw-page-title-main">MAPKAPK3</span> Protein-coding gene in the species Homo sapiens

MAP kinase-activated protein kinase 3 is an enzyme that in humans is encoded by the MAPKAPK3 gene.

<span class="mw-page-title-main">MAPK11</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 11 is an enzyme that in humans is encoded by the MAPK11 gene.

<span class="mw-page-title-main">MAPK phosphatase</span>

MAPK phosphatases (MKPs) are the largest class of phosphatases involved in down-regulating Mitogen-activated protein kinases (MAPK) signaling. MAPK signalling pathways regulate multiple features of development and homeostasis. This can involve gene regulation, cell proliferation, programmed cell death and stress responses. MAPK phosphatases are therefore important regulator components of these pathways.

<span class="mw-page-title-main">MAPK13</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 13, also known as stress-activated protein kinase 4 (SAPK4), is an enzyme that in humans is encoded by the MAPK13 gene.

The interleukin-1 receptor (IL-1R) associated kinase (IRAK) family plays a crucial role in the protective response to pathogens introduced into the human body by inducing acute inflammation followed by additional adaptive immune responses. IRAKs are essential components of the Interleukin-1 receptor signaling pathway and some Toll-like receptor signaling pathways. Toll-like receptors (TLRs) detect microorganisms by recognizing specific pathogen-associated molecular patterns (PAMPs) and IL-1R family members respond the interleukin-1 (IL-1) family cytokines. These receptors initiate an intracellular signaling cascade through adaptor proteins, primarily, MyD88. This is followed by the activation of IRAKs. TLRs and IL-1R members have a highly conserved amino acid sequence in their cytoplasmic domain called the Toll/Interleukin-1 (TIR) domain. The elicitation of different TLRs/IL-1Rs results in similar signaling cascades due to their homologous TIR motif leading to the activation of mitogen-activated protein kinases (MAPKs) and the IκB kinase (IKK) complex, which initiates a nuclear factor-κB (NF-κB) and AP-1-dependent transcriptional response of pro-inflammatory genes. Understanding the key players and their roles in the TLR/IL-1R pathway is important because the presence of mutations causing the abnormal regulation of Toll/IL-1R signaling leading to a variety of acute inflammatory and autoimmune diseases.

Candidalysin is a cytolytic 31-amino acid α-helical amphipathic peptide toxin secreted by the opportunistic pathogen Candida albicans. This toxin is a fungal example of a classical virulence factor. Hyphal morphogenesis in C. albicans is associated with damage to host epithelial cells; during this process Candidalysin is released and intercalates in host membranes. Candidalysin promotes damage of oral epithelial cells and induces lactate dehydrogenase release and calcium ion influx. It is unique in the fact that it is the first peptide toxin to be identified in any human fungal pathogen.

References

  1. ↑ Cosgrove BD, Gilbert PM, Porpiglia E, Mourkioti F, Lee SP, Corbel SY, Llewellyn ME, Delp SL, Blau HM (2014). "Rejuvenation of the muscle stem cell population restores strength to injured aged muscles". Nature Medicine. 20 (3): 255–64. doi:10.1038/nm.3464. PMC   3949152 . PMID   24531378.
  2. ↑ Segalés J, Perdiguero E, Muñoz-Cánoves P (2016). "Regulation of Muscle Stem Cell Functions: A Focus on the p38 MAPK Signaling Pathway". Frontiers in Cell and Developmental Biology. 4: 91. doi: 10.3389/fcell.2016.00091 . PMC   5003838 . PMID   27626031.
  3. ↑ Han J, Lee JD, Bibbs L, Ulevitch RJ (August 1994). "A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells". Science. 265 (5173): 808–11. Bibcode:1994Sci...265..808H. doi:10.1126/science.7914033. PMID   7914033.
  4. ↑ She QB, Chen N, Dong Z (July 2000). "ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation". Journal of Biological Chemistry. 275 (27): 20444–20449. doi: 10.1074/jbc.M001020200 . PMID   10781582.
  5. ↑ Tudor C, Marchese FP, Hitti E, Aubareda A, Rawlinson L, Gaestel M, Blackshear PJ, Clark AR, Saklatvala J, Dean JL (June 2009). "The p38 MAPK pathway inhibits tristetraprolin-directed decay of interleukin-10 and pro-inflammatory mediator mRNAs in murine macrophages". FEBS Letters. 583 (12): 1933–8. doi:10.1016/j.febslet.2009.04.039. PMC   4798241 . PMID   19416727.
  6. ↑ Dusik V, Senthilan PR, Mentzel B, Hartlieb H, Wülbeck C, Yoshii T, Raabe T, Helfrich-Förster C (2014). "The MAP Kinase p38 Is Part of Drosophila melanogaster's Circadian Clock". PLOS Genetics. 10 (8): e1004565. doi: 10.1371/journal.pgen.1004565 . PMC   4140665 . PMID   25144774.
  7. ↑ Anerillas C, Abdelmohsen K, Gorospe M (2020). "Regulation of senescence traits by MAPKs". GeroScience . 42 (2): 397–408. doi:10.1007/s11357-020-00183-3. PMC   7205942 . PMID   32300964.
  8. ↑ Yan SD, Bierhaus A, Nawroth PP, Stern DM (2009). "RAGE and Alzheimer's disease: a progression factor for amyloid-beta-induced cellular perturbation?". Journal of Alzheimer's Disease. 16 (4): 833–43. doi:10.3233/JAD-2009-1030. PMC   3726270 . PMID   19387116.
  9. ↑ Bachstetter AD, Xing B, de Almeida L, Dimayuga ER, Watterson DM, Van Eldik LJ (July 2011). "Microglial p38α MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Aβ)". Journal of Neuroinflammation. 8: 79. doi: 10.1186/1742-2094-8-79 . PMC   3142505 . PMID   21733175.
  10. ↑ Zhou Z, Bachstetter AD, Späni CB, Roy SM, Watterson DM, Van Eldik LJ (April 2017). "Retention of normal glia function by an isoform-selective protein kinase inhibitor drug candidate that modulates cytokine production and cognitive outcomes". Journal of Neuroinflammation. 14 (1): 75. doi: 10.1186/s12974-017-0845-2 . PMC   5382362 . PMID   28381303.
  11. ↑ Wei S, Siegal GP (2008). "Mechanisms modulating inflammatory osteolysis: a review with insights into therapeutic targets". Pathology, Research and Practice. 204 (10): 695–706. doi:10.1016/j.prp.2008.07.002. PMC   3747958 . PMID   18757139.
  12. ↑ Barnes PJ (July 2016). "Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease". Pharmacological Reviews. 68 (3): 788–815. doi: 10.1124/pr.116.012518 . PMID   27363440.
  13. ↑ Wang S, Ding L, Ji H, Xu Z, Liu Q, Zheng Y (June 2016). "The Role of p38 MAPK in the Development of Diabetic Cardiomyopathy". International Journal of Molecular Sciences. 17 (7): E1037. doi: 10.3390/ijms17071037 . PMC   4964413 . PMID   27376265.
  14. ↑ Segalés J, Perdiguero E, Muñoz-Cánoves P (August 2016). "Regulation of Muscle Stem Cell Functions: A Focus on the p38 MAPK Signaling Pathway". Frontiers in Cell and Developmental Biology. 4: 91. doi: 10.3389/fcell.2016.00091 . PMC   5003838 . PMID   27626031.
  15. ↑ Lang E, Bissinger R, Qadri SM, Lang F (October 2017). "Suicidal death of erythrocytes in cancer and its chemotherapy: A potential target in the treatment of tumor-associated anemia". International Journal of Cancer. 141 (8): 1522–1528. doi: 10.1002/ijc.30800 . PMID   28542880.
  16. ↑ Bonney EA (May 2017). "Mapping out p38MAPK". American Journal of Reproductive Immunology. 77 (5): e12652. doi:10.1111/aji.12652. PMC   5527295 . PMID   28194826.
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  18. ↑ Ben-Hamo R, Efroni S (2013-04-11). "hsa-miR-9 and drug control over the P38 network as driving disease outcome in GBM patients". Systems Biomedicine. 1 (2): 76–83. doi: 10.4161/sysb.25815 . ISSN   2162-8130.
  19. ↑ Goldstein DM, Gabriel T (2005). "Pathway to the clinic: inhibition of P38 MAP kinase. A review of ten chemotypes selected for development". Current Topics in Medicinal Chemistry. 5 (10): 1017–29. doi:10.2174/1568026054985939. PMID   16178744.
  20. ↑ Hill RJ, Dabbagh K, Phippard D, Li C, Suttmann RT, Welch M, Papp E, Song KW, Chang KC, Leaffer D, Kim YN, Roberts RT, Zabka TS, Aud D, Dal Porto J, Manning AM, Peng SL, Goldstein DM, Wong BR (December 2008). "Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity". The Journal of Pharmacology and Experimental Therapeutics. 327 (3): 610–9. doi:10.1124/jpet.108.139006. PMID   18776065. S2CID   7079672.
  21. ↑ "Novel p38 Inhibitor Shows Promise as Anti-Inflammatory Treatment for Patients With COPD". 2010.
  22. ↑ Mellion M, Ronco L, Thompson D, Hage M, Brooks S, van Brummelen E, Pagan L, Badrising U, Van Engelen B, Groeneveld G, Cadavid D (October 2019). "O.25Phase 1 clinical trial of losmapimod in FSHD: safety, tolerability and target engagement". Neuromuscular Disorders. 29: S123. doi: 10.1016/j.nmd.2019.06.308 .


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