MAP3K5

MAP3K5
PDBに登録されている構造
PDB	オルソログ検索: RCSB PDBe PDBj
PDBのIDコード一覧
	2CLQ, 3VW6, 4BF2, 4BHN, 4BIB, 4BIC, 4BID, 4BIE
識別子
記号	MAP3K5, ASK1, MAPKKK5, MEKK5, mitogen-activated protein kinase kinase kinase 5
外部ID	OMIM: 602448 MGI: 1346876 HomoloGene: 38114 GeneCards: MAP3K5
遺伝子の位置 (ヒト)
染色体	6番染色体 (ヒト)
終点	136,792,477 bp
遺伝子の位置 (マウス)
染色体	10番染色体 (マウス)
終点	20,018,499 bp
RNA発現パターン
	; ;
	さらなる参照発現データ
遺伝子オントロジー
分子機能	• トランスフェラーゼ活性; • protein kinase activity; • ヌクレオチド結合; • protein homodimerization activity; • 金属イオン結合; • キナーゼ活性; • 血漿タンパク結合; • protein phosphatase binding; • MAP kinase kinase kinase activity; • ATP binding; • プロテインキナーゼ結合; • magnesium ion binding; • protein serine/threonine kinase activity; • protein domain specific binding; • identical protein binding;
細胞の構成要素	• 細胞質; • protein kinase complex; • 小胞体; • IRE1-TRAF2-ASK1 complex; • 細胞質基質; • external side of plasma membrane; • 高分子複合体;
生物学的プロセス	• intrinsic apoptotic signaling pathway in response to oxidative stress; • positive regulation of protein phosphorylation; • リン酸化; • 免疫系プロセス; • regulation of cell death; • positive regulation of neuron death; • positive regulation of JNK cascade; • response to endoplasmic reticulum stress; • cellular response to reactive nitrogen species; • MAPK cascade; • タンパク質リン酸化; • JNK cascade; • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; • response to ischemia; • positive regulation of myoblast differentiation; • positive regulation of apoptotic process; • apoptotic signaling pathway; • p38MAPK cascade; • programmed necrotic cell death; • 自然免疫; • viral process; • cellular response to hydrogen peroxide; • アポトーシス; • cellular response to tumor necrosis factor; • positive regulation of cardiac muscle cell apoptotic process; • positive regulation of p38MAPK cascade; • 傷の治癒; • positive regulation of JUN kinase activity; • positive regulation of vascular associated smooth muscle cell proliferation; • endothelial cell apoptotic process; • cellular response to amino acid starvation; • positive regulation of transcription, DNA-templated; • stress-activated MAPK cascade;
	出典:Amigo / QuickGO
オルソログ
	4217
	26408
	ENSG00000197442
	ENSMUSG00000071369
	Q99683
	O35099
	NM_005923
	NM_008580
	NP_005914
	NP_032606
	ウィキデータ
閲覧/編集ヒト	閲覧/編集マウス

MAP3K5（mitogen-activated protein kinase kinase kinase 5）またはASK1（apoptosis signal-regulating kinase 1）は、MAPキナーゼ経路の一部を構成するMAPキナーゼキナーゼキナーゼである。MAP3K5は、酸化ストレス、小胞体ストレス、カルシウムの流入など一連のストレスに応答して、Raf非依存的にJNKとp38 MAPKを活性化する。MAP3K5は、がん、糖尿病、関節リウマチ、心血管疾患、神経変性疾患に関与していることが知られている^[5]^[6]。

MAP3K5タンパク質をコードするMAP3K5遺伝子は、6番染色体（英語版）の6q22.33に位置する^[7]。ノーザンブロット解析によって、MAP3K5の転写産物はヒトでは心臓と膵臓に豊富に存在することが示されている^[8]。

作用機序

非ストレス状態では、MAP3K5はC末端のコイルドコイルドメイン（CCC）を介してオリゴマー化している（このことは活性化の必要条件である）が、還元型チオレドキシン（Trx）やCIB1（英語版）の抑制作用によって不活性型となっている^[9]。TrxはN末端のコイルドコイルドメイン（NCC）に直接結合することで、MAP3K5のキナーゼ活性を阻害している。TrxとCIB1は、それぞれ酸化還元状態、カルシウム感受的な形でMAP3K5の活性化を調節している。どちらもMAP3K5の活性化因子であるTRAF2（英語版）と競合しているようである。TRAF2とTRAF6（英語版）はMAP3K5へリクルートされ、より大きな分子量の複合体を形成する^[10]。その後、MAP3K5はCCCだけでなくNCCも介したホモオリゴマー相互作用を形成し、スレオニン845番の自己リン酸化によって完全に活性化される^[11]。

MAP3K5遺伝子の転写はIL-1やTNF-αなどの炎症性サイトカインによって、NF-κBタンパク質RelA（英語版）の活性化を介して誘導される^[6]。TNF-αは、MAP3K5タンパク質を脱ユビキチン化によって安定化することもできる^[12]。このように、MAP3K5の発現は転写段階だけでなく、翻訳後段階でも調節されている^[6]。

相互作用

MAP3K5は次に挙げる因子と相互作用することが示されている。

研究

MAP3K5は筋萎縮性側索硬化症（ALS）の治療標的の1つとなる可能性がある。MAP3K5は家族性ALSと孤発性ALSの双方でアップレギュレーションされていることがAIを活用した生物学的標的発見プラットフォームを用いて発見された。標的の発見に伴って、ALSの治療のためにいくつかの経路の解析や薬剤の設計が行われている^[28]。

出典

^ ^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:
^ Mouse PubMed Reference:
^ “The roles of ASK family proteins in stress responses and diseases”. Cell Communication and Signaling 7: 9. (April 2009). doi:10.1186/1478-811X-7-9. PMC 2685135. PMID 19389260.
^ ^a ^b ^c “Regulation and function of apoptosis signal-regulating kinase 1 in rheumatoid arthritis”. Biochemical Pharmacology 151: 282–290. (May 2018). doi:10.1016/j.bcp.2018.01.041. PMID 29408488.
^ “Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5”. Cytogenetics and Cell Genetics 78 (3–4): 301–3. (1997). doi:10.1159/000134677. PMID 9465908.
^ “Entrez Gene: MAP3K5 mitogen-activated protein kinase kinase kinase 5”. 2022年11月19日閲覧。
^ “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. (October 2009). Bibcode: 2009PNAS..10617389Y. doi:10.1073/pnas.0812259106. PMC 2762684. PMID 19805025.
^ “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. (November 2005). doi:10.1074/jbc.M506771200. PMID 16129676.
^ “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. (December 2007). doi:10.1128/MCB.00227-07. PMC 2169188. PMID 17724081.
^ “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. (March 2006). doi:10.1074/jbc.M512338200. PMID 16407264.
^ “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. (July 2001). Bibcode: 2001PNAS...98.7783C. doi:10.1073/pnas.141224398. PMC 35419. PMID 11427728.
^ “The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1”. Molecular and Cellular Biology 21 (14): 4818–28. (July 2001). doi:10.1128/MCB.21.14.4818-4828.2001. PMC 87174. PMID 11416155.
^ “Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx”. Science 281 (5384): 1860–3. (September 1998). Bibcode: 1998Sci...281.1860C. doi:10.1126/science.281.5384.1860. PMID 9743501.
^ “Scaffold role of a mitogen-activated protein kinase phosphatase, SKRP1, for the JNK signaling pathway”. The Journal of Biological Chemistry 277 (26): 23919–26. (June 2002). doi:10.1074/jbc.M200838200. PMID 11959862.
^ “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. (December 2002). doi:10.1046/j.1432-1033.2002.03325.x. PMID 12473108.
^ “Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2”. Nature Cell Biology 6 (2): 146–53. (February 2004). doi:10.1038/ncb1093. PMID 14743220.
^ “Heat shock protein hsp72 is a negative regulator of apoptosis signal-regulating kinase 1”. Molecular and Cellular Biology 22 (22): 7721–30. (November 2002). doi:10.1128/MCB.22.22.7721-7730.2002. PMC 134722. PMID 12391142.
^ ^a ^b “Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress”. The EMBO Journal 20 (21): 6028–36. (November 2001). doi:10.1093/emboj/20.21.6028. PMC 125685. PMID 11689443.
^ “Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1)”. Molecular Cell 11 (6): 1491–501. (June 2003). doi:10.1016/S1097-2765(03)00180-1. PMID 12820963.
^ ^a ^b “ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction”. The Journal of Biological Chemistry 275 (42): 32747–52. (October 2000). doi:10.1074/jbc.M003042200. PMID 10921914.
^ “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. (October 2002). doi:10.1074/jbc.M202004200. PMID 12189133.
^ “Interaction of ALG-2 with ASK1 influences ASK1 localization and subsequent JNK activation”. FEBS Letters 529 (2–3): 183–7. (October 2002). doi:10.1016/S0014-5793(02)03329-X. PMID 12372597.
^ ^a ^b “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. (October 2006). doi:10.1083/jcb.200604129. PMC 2064504. PMID 17015619.
^ ^a ^b ^c “ASK1 is essential for JNK/SAPK activation by TRAF2”. Molecular Cell 2 (3): 389–95. (September 1998). doi:10.1016/S1097-2765(00)80283-X. PMID 9774977.
^ ^a ^b “Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1)”. Oncogene 18 (42): 5814–20. (October 1999). doi:10.1038/sj.onc.1202975. PMID 10523862.
^ Pun, Frank W.; Liu, Bonnie Hei Man; Long, Xi; Leung, Hoi Wing; Leung, Geoffrey Ho Duen; Mewborne, Quinlan T.; Gao, Junli; Shneyderman, Anastasia et al. (2022). “Identification of Therapeutic Targets for Amyotrophic Lateral Sclerosis Using PandaOmics – An AI-Enabled Biological Target Discovery Platform”. Frontiers in Aging Neuroscience 14: 914017. doi:10.3389/fnagi.2022.914017. ISSN 1663-4365. PMC 9273868. PMID 35837482.

外部リンク

Human MAP3K5 genome location and MAP3K5 gene details page in the UCSC Genome Browser.
Overview of all the structural information available in the PDB for UniProt: Q99683 (Mitogen-activated protein kinase kinase kinase 5) at the PDBe-KB.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000197442 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000071369 - Ensembl, May 2017

[3] Human PubMed Reference:

[4] Mouse PubMed Reference:

[pmid19389260-5] “The roles of ASK family proteins in stress responses and diseases”. Cell Communication and Signaling 7: 9. (April 2009). doi:10.1186/1478-811X-7-9. PMC 2685135. PMID 19389260.

[:0-6] “Regulation and function of apoptosis signal-regulating kinase 1 in rheumatoid arthritis”. Biochemical Pharmacology 151: 282–290. (May 2018). doi:10.1016/j.bcp.2018.01.041. PMID 29408488.

[pmid9465908-7] “Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5”. Cytogenetics and Cell Genetics 78 (3–4): 301–3. (1997). doi:10.1159/000134677. PMID 9465908.

[:1-8] “Entrez Gene: MAP3K5 mitogen-activated protein kinase kinase kinase 5”. 2022年11月19日閲覧。

[pmid19805025-9] “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. (October 2009). Bibcode: 2009PNAS..10617389Y. doi:10.1073/pnas.0812259106. PMC 2762684. PMID 19805025.

[pmid16129676-10] “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. (November 2005). doi:10.1074/jbc.M506771200. PMID 16129676.

[pmid17724081-11] “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. (December 2007). doi:10.1128/MCB.00227-07. PMC 2169188. PMID 17724081.

[:2-12] “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. (March 2006). doi:10.1074/jbc.M512338200. PMID 16407264.

[pmid11427728-13] “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. (July 2001). Bibcode: 2001PNAS...98.7783C. doi:10.1073/pnas.141224398. PMC 35419. PMID 11427728.

[pmid11416155-14] “The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1”. Molecular and Cellular Biology 21 (14): 4818–28. (July 2001). doi:10.1128/MCB.21.14.4818-4828.2001. PMC 87174. PMID 11416155.

[pmid9743501-15] “Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx”. Science 281 (5384): 1860–3. (September 1998). Bibcode: 1998Sci...281.1860C. doi:10.1126/science.281.5384.1860. PMID 9743501.

[pmid11959862-16] “Scaffold role of a mitogen-activated protein kinase phosphatase, SKRP1, for the JNK signaling pathway”. The Journal of Biological Chemistry 277 (26): 23919–26. (June 2002). doi:10.1074/jbc.M200838200. PMID 11959862.

[pmid12473108-17] “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. (December 2002). doi:10.1046/j.1432-1033.2002.03325.x. PMID 12473108.

[pmid14743220-18] “Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2”. Nature Cell Biology 6 (2): 146–53. (February 2004). doi:10.1038/ncb1093. PMID 14743220.

[pmid12391142-19] “Heat shock protein hsp72 is a negative regulator of apoptosis signal-regulating kinase 1”. Molecular and Cellular Biology 22 (22): 7721–30. (November 2002). doi:10.1128/MCB.22.22.7721-7730.2002. PMC 134722. PMID 12391142.

[pmid11689443-20] “Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress”. The EMBO Journal 20 (21): 6028–36. (November 2001). doi:10.1093/emboj/20.21.6028. PMC 125685. PMID 11689443.

[pmid12820963-21] “Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1)”. Molecular Cell 11 (6): 1491–501. (June 2003). doi:10.1016/S1097-2765(03)00180-1. PMID 12820963.

[pmid10921914-22] “ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction”. The Journal of Biological Chemistry 275 (42): 32747–52. (October 2000). doi:10.1074/jbc.M003042200. PMID 10921914.

[pmid12189133-23] “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. (October 2002). doi:10.1074/jbc.M202004200. PMID 12189133.

[pmid12372597-24] “Interaction of ALG-2 with ASK1 influences ASK1 localization and subsequent JNK activation”. FEBS Letters 529 (2–3): 183–7. (October 2002). doi:10.1016/S0014-5793(02)03329-X. PMID 12372597.

[pmid17015619-25] “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. (October 2006). doi:10.1083/jcb.200604129. PMC 2064504. PMID 17015619.

[pmid9774977-26] “ASK1 is essential for JNK/SAPK activation by TRAF2”. Molecular Cell 2 (3): 389–95. (September 1998). doi:10.1016/S1097-2765(00)80283-X. PMID 9774977.

[pmid10523862-27] “Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1)”. Oncogene 18 (42): 5814–20. (October 1999). doi:10.1038/sj.onc.1202975. PMID 10523862.

[:3-28] Pun, Frank W.; Liu, Bonnie Hei Man; Long, Xi; Leung, Hoi Wing; Leung, Geoffrey Ho Duen; Mewborne, Quinlan T.; Gao, Junli; Shneyderman, Anastasia et al. (2022). “Identification of Therapeutic Targets for Amyotrophic Lateral Sclerosis Using PandaOmics – An AI-Enabled Biological Target Discovery Platform”. Frontiers in Aging Neuroscience 14: 914017. doi:10.3389/fnagi.2022.914017. ISSN 1663-4365. PMC 9273868. PMID 35837482.

[1]

作用機序

相互作用

研究

出典

関連文献

外部リンク