Protein-coding gene in the species Homo sapiens
Apoptosis signal-regulating kinase 1 (ASK1 ) also known asmitogen-activated protein kinase kinase kinase 5 (MAP3K5 ) is a member of MAP kinase family and as such a part ofmitogen-activated protein kinase pathway. It activatesc-Jun N-terminal kinase (JNK) andp38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such asoxidative stress ,endoplasmic reticulum stress and calcium influx. ASK1 has been found to be involved in cancer, diabetes,rheumatoid arthritis , cardiovascular and neurodegenerative diseases.[ 5] [ 6]
MAP3K5 gene coding for the protein is located on chromosome 6 atlocus 6q22.33.[ 7] [citation needed Northern blot analysis shows that MAP3K5 transcript is abundant in human heart and pancreas.[ 8]
Mechanism of activation [ edit ] Under nonstress conditions ASK1 is oligomerized (a requirement for its activation) through its C-terminalcoiled-coil domain (CCC), but remains in an inactive form by the suppressive effect of reduced thioredoxin (Trx ) and calcium and integrin binding protein 1 (CIB1 ).[ 9] TRAF2 andTRAF6 are then recruited to ASK1 to form a larger molecular mass complex.[ 10] [ 11]
ASK1 gene transcription can be induced by inflammatory cytokines such as IL-1 and TNF-α through the activation of theNF-kb protein RelA.[ 6] TNF-α is also able to stabilize the ASK1 protein throughdeubiquitination .[ 12] post-transcriptional .[ 6]
ASK1 has been shown tointeract with:
C-Raf ,[ 13] CDC25A ,[ 14] DAXX ,[ 15] DUSP19 ,[ 16] EIF2AK2 ,[ 17] GADD45B ,[ 18] HSPA1A ,[ 19] MAP2K6 ,[ 20] [ 21] MAP3K7 [ 22] MAPK8IP3 ,[ 23] PDCD6 ,[ 24] PPP5C ,[ 20] RB1CC1 ,[ 25] TRAF2 ,[ 25] [ 26] TRAF5 ,[ 26] [ 27] TRAF6 .[ 22] [ 26] [ 27] ^a b c GRCh38: Ensembl release 89: ENSG00000197442 –Ensembl , May 2017^a b c GRCm38: Ensembl release 89: ENSMUSG00000071369 –Ensembl , May 2017^ "Human PubMed Reference:" .National Center for Biotechnology Information, U.S. National Library of Medicine .^ "Mouse PubMed Reference:" .National Center for Biotechnology Information, U.S. National Library of Medicine .^ Hattori K, Naguro I, Runchel C, Ichijo H (April 2009)."The roles of ASK family proteins in stress responses and diseases" .Cell Communication and Signaling .7 9.doi :10.1186/1478-811X-7-9 PMC 2685135 PMID 19389260 . ^a b c Nygaard G, Di Paolo JA, Hammaker D, Boyle DL, Budas G, Notte GT, et al. (May 2018). "Regulation and function of apoptosis signal-regulating kinase 1 in rheumatoid arthritis".Biochemical Pharmacology .151 :282– 290.doi :10.1016/j.bcp.2018.01.041 .PMID 29408488 .S2CID 4863537 . ^ Rampoldi L, Zimbello R, Bortoluzzi S, Tiso N, Valle G, Lanfranchi G, Danieli GA (1997). "Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5".Cytogenetics and Cell Genetics .78 (3– 4):301– 3.doi :10.1159/000134677 .hdl :11577/2469645 PMID 9465908 . ^ "Entrez Gene: MAP3K5 mitogen-activated protein kinase kinase kinase 5" .^ Yoon KW, Cho JH, Lee JK, Kang YH, Chae JS, Kim YM, et al. (October 2009)."CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1" .Proceedings of the National Academy of Sciences of the United States of America .106 (41):17389– 94.Bibcode :2009PNAS..10617389Y .doi :10.1073/pnas.0812259106 PMC 2762684 PMID 19805025 . ^ Noguchi T, Takeda K, Matsuzawa A, Saegusa K, Nakano H, Gohda J, et al. (November 2005)."Recruitment of tumor necrosis factor receptor-associated factor family proteins to apoptosis signal-regulating kinase 1 signalosome is essential for oxidative stress-induced cell death" .The Journal of Biological Chemistry .280 (44):37033– 40.doi :10.1074/jbc.M506771200 PMID 16129676 . ^ Fujino G, Noguchi T, Matsuzawa A, Yamauchi S, Saitoh M, Takeda K, Ichijo H (December 2007)."Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1" .Molecular and Cellular Biology .27 (23):8152– 63.doi :10.1128/MCB.00227-07 .PMC 2169188 PMID 17724081 . ^ He Y, Zhang W, Zhang R, Zhang H, Min W (March 2006)."SOCS1 inhibits tumor necrosis factor-induced activation of ASK1-JNK inflammatory signaling by mediating ASK1 degradation" .The Journal of Biological Chemistry .281 (9):5559– 66.doi :10.1074/jbc.M512338200 PMID 16407264 . ^ Chen J, Fujii K, Zhang L, Roberts T, Fu H (July 2001)."Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism" .Proceedings of the National Academy of Sciences of the United States of America .98 (14):7783– 8.Bibcode :2001PNAS...98.7783C .doi :10.1073/pnas.141224398 PMC 35419 PMID 11427728 . ^ Zou X, Tsutsui T, Ray D, Blomquist JF, Ichijo H, Ucker DS, Kiyokawa H (July 2001)."The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1" .Molecular and Cellular Biology .21 (14):4818– 28.doi :10.1128/MCB.21.14.4818-4828.2001 .PMC 87174 PMID 11416155 . ^ Chang HY , Nishitoh H, Yang X, Ichijo H, Baltimore D (September 1998). "Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx".Science .281 (5384):1860– 3.Bibcode :1998Sci...281.1860C .doi :10.1126/science.281.5384.1860 .PMID 9743501 .^ Zama T, Aoki R, Kamimoto T, Inoue K, Ikeda Y, Hagiwara M (June 2002)."Scaffold role of a mitogen-activated protein kinase phosphatase, SKRP1, for the JNK signaling pathway" .The Journal of Biological Chemistry .277 (26):23919– 26.doi :10.1074/jbc.M200838200 PMID 11959862 . ^ Takizawa T, Tatematsu C, Nakanishi Y (December 2002)."Double-stranded RNA-activated protein kinase interacts with apoptosis signal-regulating kinase 1. Implications for apoptosis signaling pathways" .European Journal of Biochemistry .269 (24):6126– 32.doi :10.1046/j.1432-1033.2002.03325.x PMID 12473108 . ^ Papa S, Zazzeroni F, Bubici C, Jayawardena S, Alvarez K, Matsuda S, et al. (February 2004). "Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2".Nature Cell Biology .6 (2):146– 53.doi :10.1038/ncb1093 .PMID 14743220 .S2CID 5250125 . ^ Park HS, Cho SG, Kim CK, Hwang HS, Noh KT, Kim MS, et al. (November 2002)."Heat shock protein hsp72 is a negative regulator of apoptosis signal-regulating kinase 1" .Molecular and Cellular Biology .22 (22):7721– 30.doi :10.1128/MCB.22.22.7721-7730.2002 .PMC 134722 PMID 12391142 . ^a b Morita K, Saitoh M, Tobiume K, Matsuura H, Enomoto S, Nishitoh H, Ichijo H (November 2001)."Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress" .The EMBO Journal .20 (21):6028– 36.doi :10.1093/emboj/20.21.6028 .PMC 125685 PMID 11689443 . ^ Huang S, Shu L, Dilling MB, Easton J, Harwood FC, Ichijo H, Houghton PJ (June 2003)."Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1)" .Molecular Cell .11 (6):1491– 501.doi :10.1016/S1097-2765(03)00180-1 PMID 12820963 . ^a b Mochida Y, Takeda K, Saitoh M, Nishitoh H, Amagasa T, Ninomiya-Tsuji J, et al. (October 2000)."ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction" .The Journal of Biological Chemistry .275 (42):32747– 52.doi :10.1074/jbc.M003042200 PMID 10921914 . ^ Matsuura H, Nishitoh H, Takeda K, Matsuzawa A, Amagasa T, Ito M, et al. (October 2002)."Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade" .The Journal of Biological Chemistry .277 (43):40703– 9.doi :10.1074/jbc.M202004200 hdl :2297/2692 PMID 12189133 . ^ Hwang IS, Jung YS, Kim E (October 2002). "Interaction of ALG-2 with ASK1 influences ASK1 localization and subsequent JNK activation".FEBS Letters .529 (2– 3):183– 7.Bibcode :2002FEBSL.529..183H .doi :10.1016/S0014-5793(02)03329-X .PMID 12372597 .S2CID 9264865 . ^a b Gan B, Peng X, Nagy T, Alcaraz A, Gu H, Guan JL (October 2006)."Role of FIP200 in cardiac and liver development and its regulation of TNFalpha and TSC-mTOR signaling pathways" .The Journal of Cell Biology .175 (1):121– 33.doi :10.1083/jcb.200604129 .PMC 2064504 PMID 17015619 . ^a b c Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, et al. (September 1998)."ASK1 is essential for JNK/SAPK activation by TRAF2" .Molecular Cell .2 (3):389– 95.doi :10.1016/S1097-2765(00)80283-X PMID 9774977 . ^a b Hoeflich KP, Yeh WC, Yao Z, Mak TW, Woodgett JR (October 1999). "Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1)".Oncogene .18 (42):5814– 20.doi :10.1038/sj.onc.1202975 .PMID 10523862 .S2CID 12132452 . Hayakawa T, Matsuzawa A, Noguchi T, Takeda K, Ichijo H (April 2006)."The ASK1-MAP kinase pathways in immune and stress responses" .Microbes and Infection .8 (4):1098– 107.doi :10.1016/j.micinf.2005.12.001 PMID 16517200 . Nagai H, Noguchi T, Takeda K, Ichijo H (January 2007)."Pathophysiological roles of ASK1-MAP kinase signaling pathways" .Journal of Biochemistry and Molecular Biology .40 (1):1– 6.doi :10.5483/BMBRep.2007.40.1.001 PMID 17244475 . Wang XS, Diener K, Jannuzzi D, Trollinger D, Tan TH, Lichenstein H, et al. (December 1996)."Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase" .The Journal of Biological Chemistry .271 (49):31607– 11.doi :10.1074/jbc.271.49.31607 PMID 8940179 . Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, et al. (January 1997). "Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways".Science .275 (5296):90– 4.doi :10.1126/science.275.5296.90 .PMID 8974401 .S2CID 23981616 . Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, et al. (May 1998)."Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1" .The EMBO Journal .17 (9):2596– 606.doi :10.1093/emboj/17.9.2596 .PMC 1170601 PMID 9564042 . Chang HY, Nishitoh H, Yang X, Ichijo H, Baltimore D (September 1998). "Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx".Science .281 (5384):1860– 3.Bibcode :1998Sci...281.1860C .doi :10.1126/science.281.5384.1860 .PMID 9743501 . Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, et al. (September 1998)."ASK1 is essential for JNK/SAPK activation by TRAF2" .Molecular Cell .2 (3):389– 95.doi :10.1016/S1097-2765(00)80283-X PMID 9774977 . Wang XS, Diener K, Tan TH, Yao Z (December 1998). "MAPKKK6, a novel mitogen-activated protein kinase kinase kinase, that associates with MAPKKK5".Biochemical and Biophysical Research Communications .253 (1):33– 7.Bibcode :1998BBRC..253...33W .doi :10.1006/bbrc.1998.9749 .PMID 9875215 . Zhang L, Chen J, Fu H (July 1999)."Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins" .Proceedings of the National Academy of Sciences of the United States of America .96 (15):8511– 5.Bibcode :1999PNAS...96.8511Z .doi :10.1073/pnas.96.15.8511 PMC 17547 PMID 10411906 . Hoeflich KP, Yeh WC, Yao Z, Mak TW, Woodgett JR (October 1999). "Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1)".Oncogene .18 (42):5814– 20.doi :10.1038/sj.onc.1202975 .PMID 10523862 .S2CID 12132452 . Takeda K, Hatai T, Hamazaki TS, Nishitoh H, Saitoh M, Ichijo H (March 2000)."Apoptosis signal-regulating kinase 1 (ASK1) induces neuronal differentiation and survival of PC12 cells" .The Journal of Biological Chemistry .275 (13):9805– 13.doi :10.1074/jbc.275.13.9805 PMID 10734135 . Charette SJ, Lavoie JN, Lambert H, Landry J (October 2000)."Inhibition of Daxx-mediated apoptosis by heat shock protein 27" .Molecular and Cellular Biology .20 (20):7602– 12.doi :10.1128/MCB.20.20.7602-7612.2000 .PMC 86317 PMID 11003656 . Ko YG, Kim EY, Kim T, Park H, Park HS, Choi EJ, Kim S (February 2001)."Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1" .The Journal of Biological Chemistry .276 (8):6030– 6.doi :10.1074/jbc.M006189200 PMID 11096076 . Kim AH, Khursigara G, Sun X, Franke TF, Chao MV (February 2001)."Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1" .Molecular and Cellular Biology .21 (3):893– 901.doi :10.1128/MCB.21.3.893-901.2001 .PMC 86680 PMID 11154276 . Cho SG, Lee YH, Park HS, Ryoo K, Kang KW, Park J, et al. (April 2001)."Glutathione S-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1" .The Journal of Biological Chemistry .276 (16):12749– 55.doi :10.1074/jbc.M005561200 PMID 11278289 . Geleziunas R, Xu W, Takeda K, Ichijo H, Greene WC (April 2001). "HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell".Nature .410 (6830):834– 8.Bibcode :2001Natur.410..834G .doi :10.1038/35071111 .PMID 11298454 .S2CID 4414424 .
Activity Regulation Classification Kinetics Types
