| Structural highlights
Function
MK13_HUMAN Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK13 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK13 is one of the less studied p38 MAPK isoforms. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in the regulation of protein translation by phosphorylating and inactivating EEF2K. Involved in cytoskeletal remodeling through phosphorylation of MAPT and STMN1. Mediates UV irradiation induced up-regulation of the gene expression of CXCL14. Plays an important role in the regulation of epidermal keratinocyte differentiation, apoptosis and skin tumor development. Phosphorylates the transcriptional activator MYB in response to stress which leads to rapid MYB degradation via a proteasome-dependent pathway. MAPK13 also phosphorylates and down-regulates PRKD1 during regulation of insulin secretion in pancreatic beta cells.[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Increased mucus production is a common cause of morbidity and mortality in inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the precise molecular mechanisms for pathogenic mucus production are largely undetermined. Accordingly, there are no specific and effective anti-mucus therapeutics. Here, we define a signaling pathway from chloride channel calcium-activated 1 (CLCA1) to MAPK13 that is responsible for IL-13-driven mucus production in human airway epithelial cells. The same pathway was also highly activated in the lungs of humans with excess mucus production due to COPD. We further validated the pathway by using structure-based drug design to develop a series of novel MAPK13 inhibitors with nanomolar potency that effectively reduced mucus production in human airway epithelial cells. These results uncover and validate a new pathway for regulating mucus production as well as a corresponding therapeutic approach to mucus overproduction in inflammatory airway diseases.
IL-13-induced airway mucus production is attenuated by MAPK13 inhibition.,Alevy YG, Patel AC, Romero AG, Patel DA, Tucker J, Roswit WT, Miller CA, Heier RF, Byers DE, Brett TJ, Holtzman MJ J Clin Invest. 2012 Dec 3;122(12):4555-68. doi: 10.1172/JCI64896. Epub 2012 Nov, 26. PMID:23187130[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Parker CG, Hunt J, Diener K, McGinley M, Soriano B, Keesler GA, Bray J, Yao Z, Wang XS, Kohno T, Lichenstein HS. Identification of stathmin as a novel substrate for p38 delta. Biochem Biophys Res Commun. 1998 Aug 28;249(3):791-6. PMID:9731215 doi:http://dx.doi.org/10.1006/bbrc.1998.9250
- ↑ Knebel A, Morrice N, Cohen P. A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. EMBO J. 2001 Aug 15;20(16):4360-9. PMID:11500363 doi:http://dx.doi.org/10.1093/emboj/20.16.4360
- ↑ Buee-Scherrer V, Goedert M. Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells. FEBS Lett. 2002 Mar 27;515(1-3):151-4. PMID:11943212
- ↑ Feijoo C, Campbell DG, Jakes R, Goedert M, Cuenda A. Evidence that phosphorylation of the microtubule-associated protein Tau by SAPK4/p38delta at Thr50 promotes microtubule assembly. J Cell Sci. 2005 Jan 15;118(Pt 2):397-408. Epub 2005 Jan 4. PMID:15632108 doi:http://dx.doi.org/10.1242/jcs.01655
- ↑ Kraft CA, Efimova T, Eckert RL. Activation of PKCdelta and p38delta MAPK during okadaic acid dependent keratinocyte apoptosis. Arch Dermatol Res. 2007 May;299(2):71-83. Epub 2007 Jan 26. PMID:17256148 doi:http://dx.doi.org/10.1007/s00403-006-0727-4
- ↑ Pani E, Ferrari S. p38MAPK delta controls c-Myb degradation in response to stress. Blood Cells Mol Dis. 2008 May-Jun;40(3):388-94. Epub 2007 Nov 19. PMID:18006338 doi:http://dx.doi.org/10.1016/j.bcmd.2007.09.010
- ↑ Zhou X, Ferraris JD, Dmitrieva NI, Liu Y, Burg MB. MKP-1 inhibits high NaCl-induced activation of p38 but does not inhibit the activation of TonEBP/OREBP: opposite roles of p38alpha and p38delta. Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5620-5. doi:, 10.1073/pnas.0801453105. Epub 2008 Mar 26. PMID:18367666 doi:http://dx.doi.org/10.1073/pnas.0801453105
- ↑ Ozawa S, Ito S, Kato Y, Kubota E, Hata R. Human p38 delta MAP kinase mediates UV irradiation induced up-regulation of the gene expression of chemokine BRAK/CXCL14. Biochem Biophys Res Commun. 2010 Jun 11;396(4):1060-4. doi:, 10.1016/j.bbrc.2010.05.072. Epub 2010 May 15. PMID:20478268 doi:http://dx.doi.org/10.1016/j.bbrc.2010.05.072
- ↑ Alevy YG, Patel AC, Romero AG, Patel DA, Tucker J, Roswit WT, Miller CA, Heier RF, Byers DE, Brett TJ, Holtzman MJ. IL-13-induced airway mucus production is attenuated by MAPK13 inhibition. J Clin Invest. 2012 Dec 3;122(12):4555-68. doi: 10.1172/JCI64896. Epub 2012 Nov, 26. PMID:23187130 doi:http://dx.doi.org/10.1172/JCI64896
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