MAPKAPK2

MAPKAPK2
Estruturas disponíveis
PDB	Pesquisa Human UniProt: PDBe RCSB
Lista de códigos id do PDB
	1KWP, 1NXK, 1NY3, 2JBO, 2JBP, 2OKR, 2ONL, 2OZA, 2P3G, 2PZY, 3A2C, 3FPM, 3FYJ, 3FYK, 3GOK, 3KA0, 3KC3, 3KGA, 3M2W, 3M42, 3R2B, 3R2Y, 3R30, 3WI6, 4TYH
Identificadores
Nomes alternativos	MAPKAPK2
IDs externos	OMIM: 602006 HomoloGene: 56412 GeneCards: MAPKAPK2
Número EC	2.7.11.1
Ontologia genética
Função molecular	• calmodulin-dependent protein kinase activity; • signal transducer activity; • nucleotide binding; • transferase activity; • kinase activity; • calcium-dependent protein serine/threonine kinase activity; • calmodulin binding; • ATP binding; • GO:0001948, GO:0016582 ligação a proteínas plasmáticas; • protein kinase activity; • protein serine/threonine kinase activity; • mitogen-activated protein kinase binding;
Componente celular	• Exossoma; • citosol; • centrossoma; • cariolinfa; • citoplasma; • núcleo celular;
Processo biológico	• response to stress; • MAPK cascade; • regulation of mRNA stability; • response to cytokine; • GO:0035404 peptidyl-serine phosphorylation; • cellular response to vascular endothelial growth factor stimulus; • mRNA stabilization; • Autofosforilação; • 3'-UTR-mediated mRNA stabilization; • cellular response to DNA damage stimulus; • inner ear development; • p38MAPK cascade; • Ras protein signal transduction; • leukotriene metabolic process; • regulation of cellular response to heat; • fosforilação; • protein phosphorylation; • regulation of interleukin-6 production; • vascular endothelial growth factor receptor signaling pathway; • response to lipopolysaccharide; • inflammatory response; • macropinocytosis; • regulation of tumor necrosis factor production; • toll-like receptor signaling pathway; • GO:0007243 intracellular signal transduction;
	Sources:Amigo / QuickGO
Padrão de expressão RNA
	; ; ; ;
	Mais dados de referência de expressão
Ortólogos
	9261
	n/a
	ENSG00000162889
	n/a
	P49137
	n/a
	NM_004759; NM_032960
	n/a
	NP_004750; NP_116584
	n/a
	Wikidata
Ver/Editar Humano

Proteína quinase 2 ativada por MAP quinase é uma enzima que em humanos é codificada pelo gene MAPKAPK2.

Função

Este gene codifica um membro da família de proteínas quinases Ser/Thr [en]. Esta quinase é regulada através de fosforilação direta pela quinase p38 MAP [en]. Em conjunto com a quinase p38 MAP, esta quinase é conhecida por estar envolvida em muitos processos celulares, incluindo estresse e respostas inflamatórias, exportação nuclear, regulação da expressão gênica e proliferação celular. A proteína de choque térmico HSP27 [en] demonstrou ser seu principal substrato direto in vivo. Duas variantes de transcrição codificando duas isoformas diferentes foram encontradas para este gene.

Barreira vascular

A via MK2 demonstrou ter um papel fundamental na manutenção e reparo da integridade da barreira endotelial no pulmão via actina e remodelação de vimentina. A ativação de MK2 via sua fosforilação por p38 demonstrou restaurar a barreira vascular e reparar o vazamento vascular, associado a mais de 60 condições médicas, incluindo a Síndrome do Desconforto Respiratório Agudo (SDRA), uma das principais causas de morte em todo o mundo.

Iniciação do SASP

A MAPKAPK2 media a iniciação do fenótipo secretor associado à senescência (SASP) pelo mTOR (alvo mecanicista da rapamicina). A Interleucina 1 alfa [en] (IL1A) é encontrada na superfície de células senescentes, onde contribui para a produção de fatores SASP devido a uma alça de feedback positivo com NF-κB. A tradução do mRNA para IL1A é altamente dependente da atividade do mTOR. A atividade do mTOR aumenta os níveis de IL1A, mediada por MAPKAPK2.

Interações

Demonstrou-se que MAPKAPK2 interage com:

AKT1,
MAPK14 [en],
PHC2 [en],
SHC1 [en], e
RIPK1 [en].

Referências

↑ «Human PubMed Reference:»
↑ Zu YL, Wu F, Gilchrist A, Ai Y, Labadia ME, Huang CK (Abril de 1994). «The primary structure of a human MAP kinase activated protein kinase 2». Biochemical and Biophysical Research Communications. 200 (2): 1118–24. Bibcode:1994BBRC..200.1118Z. PMID 8179591. doi:10.1006/bbrc.1994.1566
↑ Stokoe D, Caudwell B, Cohen PT, Cohen P (Dezembro de 1993). «The substrate specificity and structure of mitogen-activated protein (MAP) kinase-activated protein kinase-2». The Biochemical Journal. 296 ( Pt 3) (Pt 3): 843–9. PMC 1137771. PMID 8280084. doi:10.1042/bj2960843
1 2 Liu T, Warburton RR, Hill NS, Kayyali US (Agosto de 2015). «Anthrax lethal toxin-induced lung injury and treatment by activating MK2». Journal of Applied Physiology. 119 (4): 412–9. PMC 4538279. PMID 26066827. doi:10.1152/japplphysiol.00335.2015
↑ «Entrez Gene: MAPKAPK2 mitogen-activated protein kinase-activated protein kinase 2»
↑ Sousa AM, Liu T, Guevara O, Stevens J, Fanburg BL, Gaestel M, Toksoz D, Kayyali US (Abril de 2007). «Smooth muscle alpha-actin expression and myofibroblast differentiation by TGFbeta are dependent upon MK2». Journal of Cellular Biochemistry. 100 (6): 1581–92. PMC 2586991. PMID 17163490. doi:10.1002/jcb.21154
↑ Liu T, Milia E, Warburton RR, Hill NS, Gaestel M, Kayyali US (Abril de 2012). «Anthrax lethal toxin disrupts the endothelial permeability barrier through blocking p38 signaling». Journal of Cellular Physiology. 227 (4): 1438–45. PMC 4254851. PMID 21618534. doi:10.1002/jcp.22859
↑ Pham T, Rubenfeld GD (Abril de 2017). «Fifty Years of Research in ARDS. The Epidemiology of Acute Respiratory Distress Syndrome. A 50th Birthday Review». American Journal of Respiratory and Critical Care Medicine. 195 (7): 860–870. PMID 28157386. doi:10.1164/rccm.201609-1773CP
↑ Yessenkyzy A, Saliev T, Zhanaliyeva M, Masoud AR, Umbayev B, Sergazy S, Krivykh E, Gulyayev A, Nurgozhin T (Maio de 2020). «Polyphenols as Caloric-Restriction Mimetics and Autophagy Inducers in Aging Research». Nutrients. 12 (5). 1344 páginas. PMC 7285205. PMID 32397145. doi:10.3390/nu12051344
↑ Papadopoli D, Boulay K, Kazak L, Pollak M, Mallette F, Topisirovic I, Hulea L (2019). «mTOR as a central regulator of lifespan and aging». F1000Research. 8: 998. PMC 6611156. PMID 31316753. doi:10.12688/f1000research.17196.1
1 2 Laberge RM, Sun Y, Orjalo AV, Patil CK, Freund A, Zhou L, Curran SC, Davalos AR, Wilson-Edell KA, Liu S, Limbad C, Demaria M, Li P, Hubbard GB, Ikeno Y, Javors M, Desprez PY, Benz CC, Kapahi P, Nelson PS, Campisi J (Agosto de 2015). «MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation». Nature Cell Biology. 17 (8): 1049–61. PMC 4691706. PMID 26147250. doi:10.1038/ncb3195
↑ Wang R, Yu Z, Sunchu B, Shoaf J, Dang I, Zhao S, Caples K, Bradley L, Beaver LM, Ho E, Löhr CV, Perez VI (Junho de 2017). «Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism». Aging Cell. 16 (3): 564–574. PMC 5418203. PMID 28371119. doi:10.1111/acel.12587
↑ Wang R, Sunchu B, Perez VI (Agosto de 2017). «Rapamycin and the inhibition of the secretory phenotype». Experimental Gerontology. 94: 89–92. PMID 28167236. doi:10.1016/j.exger.2017.01.026
1 2 Rane MJ, Coxon PY, Powell DW, Webster R, Klein JB, Pierce W, Ping P, McLeish KR (Fevereiro de 2001). «p38 Kinase-dependent MAPKAPK-2 activation functions as 3-phosphoinositide-dependent kinase-2 for Akt in human neutrophils». The Journal of Biological Chemistry. 276 (5): 3517–23. PMID 11042204. doi:10.1074/jbc.M005953200
↑ Janknecht R (Novembro de 2001). «Cell type-specific inhibition of the ETS transcription factor ER81 by mitogen-activated protein kinase-activated protein kinase 2». The Journal of Biological Chemistry. 276 (45): 41856–61. PMID 11551945. doi:10.1074/jbc.M106630200
1 2 Yannoni YM, Gaestel M, Lin LL (Abril de 2004). «P66(ShcA) interacts with MAPKAP kinase 2 and regulates its activity». FEBS Letters. 564 (1–2): 205–11. Bibcode:2004FEBSL.564..205Y. PMID 15094067. doi:10.1016/S0014-5793(04)00351-5
↑ Dondelinger Y, Delanghe T, Rojas-Rivera D, Priem D, Delvaeye T, Bruggeman I, Van Herreweghe F, Vandenabeele P, Bertrand MJ (Outubro de 2017). «MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death». Nature Cell Biology. 19 (10): 1237–1247. PMID 28920952. doi:10.1038/ncb3608

Leitura adicional

Kapopara PR, von Felden J, Soehnlein O, Wang Y, Napp LC, Sonnenschein K, Wollert KC, Schieffer B, Gaestel M, Bauersachs J, Bavendiek U (Dezembro de 2014). «Deficiency of MAPK-activated protein kinase 2 (MK2) prevents adverse remodelling and promotes endothelial healing after arterial injury». Thrombosis and Haemostasis. 112 (6): 1264–76. PMID 25120198. doi:10.1160/TH14-02-0174
Ben-Levy R, Hooper S, Wilson R, Paterson HF, Marshall CJ (Setembro de 1998). «Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2». Current Biology. 8 (19): 1049–57. Bibcode:1998CBio....8.1049B. PMID 9768359. doi:10.1016/S0960-9822(98)70442-7
Stokoe D, Engel K, Campbell DG, Cohen P, Gaestel M (Novembro de 1992). «Identification of MAPKAP kinase 2 as a major enzyme responsible for the phosphorylation of the small mammalian heat shock proteins». FEBS Letters. 313 (3): 307–13. Bibcode:1992FEBSL.313..307S. PMID 1332886. doi:10.1016/0014-5793(92)81216-9
Vulliet PR, Woodgett JR, Cohen P (Novembro de 1984). «Phosphorylation of tyrosine hydroxylase by calmodulin-dependent multiprotein kinase». The Journal of Biological Chemistry. 259 (22): 13680–3. PMID 6150037. doi:10.1016/S0021-9258(18)89798-8
Engel K, Schultz H, Martin F, Kotlyarov A, Plath K, Hahn M, Heinemann U, Gaestel M (Novembro de 1995). «Constitutive activation of mitogen-activated protein kinase-activated protein kinase 2 by mutation of phosphorylation sites and an A-helix motif». The Journal of Biological Chemistry. 270 (45): 27213–21. PMID 7592979. doi:10.1074/jbc.270.45.27213
Lavoie JN, Lambert H, Hickey E, Weber LA, Landry J (Janeiro de 1995). «Modulation of cellular thermoresistance and actin filament stability accompanies phosphorylation-induced changes in the oligomeric structure of heat shock protein 27». Molecular and Cellular Biology. 15 (1): 505–16. PMC 232001. PMID 7799959. doi:10.1128/MCB.15.1.505
Sutherland C, Alterio J, Campbell DG, Le Bourdellès B, Mallet J, Haavik J, Cohen P (Outubro de 1993). «Phosphorylation and activation of human tyrosine hydroxylase in vitro by mitogen-activated protein (MAP) kinase and MAP-kinase-activated kinases 1 and 2». European Journal of Biochemistry. 217 (2): 715–22. PMID 7901013. doi:10.1111/j.1432-1033.1993.tb18297.x
Knauf U, Jakob U, Engel K, Buchner J, Gaestel M (Janeiro de 1994). «Stress- and mitogen-induced phosphorylation of the small heat shock protein Hsp25 by MAPKAP kinase 2 is not essential for chaperone properties and cellular thermoresistance». The EMBO Journal. 13 (1): 54–60. PMC 394778. PMID 7905823. doi:10.1002/j.1460-2075.1994.tb06234.x
Freshney NW, Rawlinson L, Guesdon F, Jones E, Cowley S, Hsuan J, Saklatvala J (Setembro de 1994). «Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27». Cell. 78 (6): 1039–49. PMID 7923354. doi:10.1016/0092-8674(94)90278-X
Rivera VM, Miranti CK, Misra RP, Ginty DD, Chen RH, Blenis J, Greenberg ME (Outubro de 1993). «A growth factor-induced kinase phosphorylates the serum response factor at a site that regulates its DNA-binding activity». Molecular and Cellular Biology. 13 (10): 6260–73. PMC 364685. PMID 8413226. doi:10.1128/mcb.13.10.6260
Beyaert R, Cuenda A, Vanden Berghe W, Plaisance S, Lee JC, Haegeman G, Cohen P, Fiers W (Abril de 1996). «The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis response to tumor necrosis factor». The EMBO Journal. 15 (8): 1914–23. PMC 450110. PMID 8617238. doi:10.1002/j.1460-2075.1996.tb00542.x
Ben-Levy R, Leighton IA, Doza YN, Attwood P, Morrice N, Marshall CJ, Cohen P (Dezembro de 1995). «Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2». The EMBO Journal. 14 (23): 5920–30. PMC 394711. PMID 8846784. doi:10.1002/j.1460-2075.1995.tb00280.x
Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ (Setembro de 1996). «FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2». The EMBO Journal. 15 (17): 4629–42. PMC 452194. PMID 8887554. doi:10.1002/j.1460-2075.1996.tb00840.x
Huang CK, Zhan L, Ai Y, Jongstra J (Janeiro de 1997). «LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils». The Journal of Biological Chemistry. 272 (1): 17–9. PMID 8995217. doi:10.1074/jbc.272.1.17
Krump E, Sanghera JS, Pelech SL, Furuya W, Grinstein S (Janeiro de 1997). «Chemotactic peptide N-formyl-met-leu-phe activation of p38 mitogen-activated protein kinase (MAPK) and MAPK-activated protein kinase-2 in human neutrophils». The Journal of Biological Chemistry. 272 (2): 937–44. PMID 8995385. doi:10.1074/jbc.272.2.937
Engel K, Kotlyarov A, Gaestel M (Junho de 1998). «Leptomycin B-sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation». The EMBO Journal. 17 (12): 3363–71. PMC 1170674. PMID 9628873. doi:10.1093/emboj/17.12.3363
Craxton A, Shu G, Graves JD, Saklatvala J, Krebs EG, Clark EA (Outubro de 1998). «p38 MAPK is required for CD40-induced gene expression and proliferation in B lymphocytes». Journal of Immunology. 161 (7): 3225–36. PMID 9759836. doi:10.4049/jimmunol.161.7.3225
Heidenreich O, Neininger A, Schratt G, Zinck R, Cahill MA, Engel K, Kotlyarov A, Kraft R, Kostka S, Gaestel M, Nordheim A (Maio de 1999). «MAPKAP kinase 2 phosphorylates serum response factor in vitro and in vivo». The Journal of Biological Chemistry. 274 (20): 14434–43. PMID 10318869. doi:10.1074/jbc.274.20.14434

[1] «Human PubMed Reference:»

[pmid8179591-2] Zu YL, Wu F, Gilchrist A, Ai Y, Labadia ME, Huang CK (Abril de 1994). «The primary structure of a human MAP kinase activated protein kinase 2». Biochemical and Biophysical Research Communications. 200 (2): 1118–24. Bibcode:1994BBRC..200.1118Z. PMID 8179591. doi:10.1006/bbrc.1994.1566

[pmid8280084-3] Stokoe D, Caudwell B, Cohen PT, Cohen P (Dezembro de 1993). «The substrate specificity and structure of mitogen-activated protein (MAP) kinase-activated protein kinase-2». The Biochemical Journal. 296 ( Pt 3) (Pt 3): 843–9. PMC 1137771. PMID 8280084. doi:10.1042/bj2960843

[Liu_412–419-4] 1 2 Liu T, Warburton RR, Hill NS, Kayyali US (Agosto de 2015). «Anthrax lethal toxin-induced lung injury and treatment by activating MK2». Journal of Applied Physiology. 119 (4): 412–9. PMC 4538279. PMID 26066827. doi:10.1152/japplphysiol.00335.2015

[entrez-5] «Entrez Gene: MAPKAPK2 mitogen-activated protein kinase-activated protein kinase 2»

[6] Sousa AM, Liu T, Guevara O, Stevens J, Fanburg BL, Gaestel M, Toksoz D, Kayyali US (Abril de 2007). «Smooth muscle alpha-actin expression and myofibroblast differentiation by TGFbeta are dependent upon MK2». Journal of Cellular Biochemistry. 100 (6): 1581–92. PMC 2586991. PMID 17163490. doi:10.1002/jcb.21154

[7] Liu T, Milia E, Warburton RR, Hill NS, Gaestel M, Kayyali US (Abril de 2012). «Anthrax lethal toxin disrupts the endothelial permeability barrier through blocking p38 signaling». Journal of Cellular Physiology. 227 (4): 1438–45. PMC 4254851. PMID 21618534. doi:10.1002/jcp.22859

[8] Pham T, Rubenfeld GD (Abril de 2017). «Fifty Years of Research in ARDS. The Epidemiology of Acute Respiratory Distress Syndrome. A 50th Birthday Review». American Journal of Respiratory and Critical Care Medicine. 195 (7): 860–870. PMID 28157386. doi:10.1164/rccm.201609-1773CP

[pmid32397145-9] Yessenkyzy A, Saliev T, Zhanaliyeva M, Masoud AR, Umbayev B, Sergazy S, Krivykh E, Gulyayev A, Nurgozhin T (Maio de 2020). «Polyphenols as Caloric-Restriction Mimetics and Autophagy Inducers in Aging Research». Nutrients. 12 (5). 1344 páginas. PMC 7285205. PMID 32397145. doi:10.3390/nu12051344

[pmid31316753-10] Papadopoli D, Boulay K, Kazak L, Pollak M, Mallette F, Topisirovic I, Hulea L (2019). «mTOR as a central regulator of lifespan and aging». F1000Research. 8: 998. PMC 6611156. PMID 31316753. doi:10.12688/f1000research.17196.1

[pmid26147250-11] 1 2 Laberge RM, Sun Y, Orjalo AV, Patil CK, Freund A, Zhou L, Curran SC, Davalos AR, Wilson-Edell KA, Liu S, Limbad C, Demaria M, Li P, Hubbard GB, Ikeno Y, Javors M, Desprez PY, Benz CC, Kapahi P, Nelson PS, Campisi J (Agosto de 2015). «MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation». Nature Cell Biology. 17 (8): 1049–61. PMC 4691706. PMID 26147250. doi:10.1038/ncb3195

[pmid28371119-12] Wang R, Yu Z, Sunchu B, Shoaf J, Dang I, Zhao S, Caples K, Bradley L, Beaver LM, Ho E, Löhr CV, Perez VI (Junho de 2017). «Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism». Aging Cell. 16 (3): 564–574. PMC 5418203. PMID 28371119. doi:10.1111/acel.12587

[pmid28167236-13] Wang R, Sunchu B, Perez VI (Agosto de 2017). «Rapamycin and the inhibition of the secretory phenotype». Experimental Gerontology. 94: 89–92. PMID 28167236. doi:10.1016/j.exger.2017.01.026

[pmid11042204-14] 1 2 Rane MJ, Coxon PY, Powell DW, Webster R, Klein JB, Pierce W, Ping P, McLeish KR (Fevereiro de 2001). «p38 Kinase-dependent MAPKAPK-2 activation functions as 3-phosphoinositide-dependent kinase-2 for Akt in human neutrophils». The Journal of Biological Chemistry. 276 (5): 3517–23. PMID 11042204. doi:10.1074/jbc.M005953200

[pmid11551945-15] Janknecht R (Novembro de 2001). «Cell type-specific inhibition of the ETS transcription factor ER81 by mitogen-activated protein kinase-activated protein kinase 2». The Journal of Biological Chemistry. 276 (45): 41856–61. PMID 11551945. doi:10.1074/jbc.M106630200

[pmid15094067-16] 1 2 Yannoni YM, Gaestel M, Lin LL (Abril de 2004). «P66(ShcA) interacts with MAPKAP kinase 2 and regulates its activity». FEBS Letters. 564 (1–2): 205–11. Bibcode:2004FEBSL.564..205Y. PMID 15094067. doi:10.1016/S0014-5793(04)00351-5

[17] Dondelinger Y, Delanghe T, Rojas-Rivera D, Priem D, Delvaeye T, Bruggeman I, Van Herreweghe F, Vandenabeele P, Bertrand MJ (Outubro de 2017). «MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death». Nature Cell Biology. 19 (10): 1237–1247. PMID 28920952. doi:10.1038/ncb3608

v d e Enzimas
Atividade	Sítio ativo Sítio de ligação Co-enzima Cofator Catálise enzimática
Controle	Inibição enzimática Ativador enzimático
Classificação	Número EC Superfamília enzimática Família de enzimas
Cinética	Cinética enzimática Diagrama de Lineweaver-Burke Cinética de Michaelis-Menten
Tipos	EC1 Oxirredutases EC2 Transferases EC3 Hidrolases EC4 Liases EC5 Isomerases EC6 Ligases