MAP3K1

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View/Edit Human

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Mitogen-activated protein kinase kinase kinase 1 is an enzyme that in humans is encoded by the MAP3K1 gene.^[1]^[2]

Function

MAP3K, or MEK kinase or Raf, is a serine/threonine kinase that occupies a pivotal role in a network of phosphorylating enzymes integrating cellular responses to a number of mitogenic and metabolic stimuli, including insulin and many growth factors.^[2]

Mouse genetics has revealed that the kinase is important in: correct embryogenesis, keratinocyte migration, T cell cytokine production and B cell antibody production.

MAP3K1 is a regulatory target of GWAS variants associated with breast cancer risk ^[3]

Interactions

MAP3K1 has been shown to interact with:

References

↑ Vinik BS, Kay ES, Fiedorek FT (November 1995). "Mapping of the MEK kinase gene (Mekk) to mouse chromosome 13 and human chromosome 5". Mammalian Genome. 6 (11): 782–3. doi:10.1007/BF00539003. PMID 8597633.
↑ ^2.0 ^2.1 "Entrez Gene: MAP3K1 mitogen-activated protein kinase kinase kinase 1".
↑ Glubb DM, Maranian MJ, Michailidou K, Pooley KA, Meyer KB, Kar S, et al. (January 2015). "Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1". American Journal of Human Genetics. 96 (1): 5–20. doi:10.1016/j.ajhg.2014.11.009. PMC 4289692. PMID 25529635.
↑ Zhang Y, Qiu WJ, Chan SC, Han J, He X, Lin SC (May 2002). "Casein kinase I and casein kinase II differentially regulate axin function in Wnt and JNK pathways". The Journal of Biological Chemistry. 277 (20): 17706–12. doi:10.1074/jbc.M111982200. PMID 11884395.
↑ Zhang Y, Neo SY, Han J, Lin SC (August 2000). "Dimerization choices control the ability of axin and dishevelled to activate c-Jun N-terminal kinase/stress-activated protein kinase". The Journal of Biological Chemistry. 275 (32): 25008–14. doi:10.1074/jbc.M002491200. PMID 10829020.
↑ ^6.0 ^6.1 ^6.2 Karandikar M, Xu S, Cobb MH (December 2000). "MEKK1 binds raf-1 and the ERK2 cascade components". The Journal of Biological Chemistry. 275 (51): 40120–7. doi:10.1074/jbc.M005926200. PMID 10969079.
↑ Pomérance M, Multon MC, Parker F, Venot C, Blondeau JP, Tocqué B, Schweighoffer F (September 1998). "Grb2 interaction with MEK-kinase 1 is involved in regulation of Jun-kinase activities in response to epidermal growth factor". The Journal of Biological Chemistry. 273 (38): 24301–4. doi:10.1074/jbc.273.38.24301. PMID 9733714.
↑ Xu S, Cobb MH (December 1997). "MEKK1 binds directly to the c-Jun N-terminal kinases/stress-activated protein kinases". The Journal of Biological Chemistry. 272 (51): 32056–60. doi:10.1074/jbc.272.51.32056. PMID 9405400.
↑ Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M (May 1999). "Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain". Genes & Development. 13 (10): 1297–308. doi:10.1101/gad.13.10.1297. PMC 316725. PMID 10346818.
↑ Saltzman A, Searfoss G, Marcireau C, Stone M, Ressner R, Munro R, Franks C, D'Alonzo J, Tocque B, Jaye M, Ivashchenko Y (April 1998). "hUBC9 associates with MEKK1 and type I TNF-alpha receptor and stimulates NFkappaB activity". FEBS Letters. 425 (3): 431–5. doi:10.1016/s0014-5793(98)00287-7. PMID 9563508.

Lee FS, Hagler J, Chen ZJ, Maniatis T (January 1997). "Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway". Cell. 88 (2): 213–22. doi:10.1016/S0092-8674(00)81842-5. PMID 9008162.
Siow YL, Kalmar GB, Sanghera JS, Tai G, Oh SS, Pelech SL (March 1997). "Identification of two essential phosphorylated threonine residues in the catalytic domain of Mekk1. Indirect activation by Pak3 and protein kinase C". The Journal of Biological Chemistry. 272 (12): 7586–94. doi:10.1074/jbc.272.12.7586. PMID 9065412.
Su YC, Han J, Xu S, Cobb M, Skolnik EY (March 1997). "NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain". The EMBO Journal. 16 (6): 1279–90. doi:10.1093/emboj/16.6.1279. PMC 1169726. PMID 9135144.
Wu Z, Wu J, Jacinto E, Karin M (December 1997). "Molecular cloning and characterization of human JNKK2, a novel Jun NH2-terminal kinase-specific kinase". Molecular and Cellular Biology. 17 (12): 7407–16. doi:10.1128/mcb.17.12.7407. PMC 232596. PMID 9372971.
Xu S, Cobb MH (December 1997). "MEKK1 binds directly to the c-Jun N-terminal kinases/stress-activated protein kinases". The Journal of Biological Chemistry. 272 (51): 32056–60. doi:10.1074/jbc.272.51.32056. PMID 9405400.
Fanger GR, Widmann C, Porter AC, Sather S, Johnson GL, Vaillancourt RR (February 1998). "14-3-3 proteins interact with specific MEK kinases". The Journal of Biological Chemistry. 273 (6): 3476–83. doi:10.1074/jbc.273.6.3476. PMID 9452471.
Hirai S, Noda K, Moriguchi T, Nishida E, Yamashita A, Deyama T, Fukuyama K, Ohno S (March 1998). "Differential activation of two JNK activators, MKK7 and SEK1, by MKN28-derived nonreceptor serine/threonine kinase/mixed lineage kinase 2". The Journal of Biological Chemistry. 273 (13): 7406–12. doi:10.1074/jbc.273.13.7406. PMID 9516438.
Saltzman A, Searfoss G, Marcireau C, Stone M, Ressner R, Munro R, Franks C, D'Alonzo J, Tocque B, Jaye M, Ivashchenko Y (April 1998). "hUBC9 associates with MEKK1 and type I TNF-alpha receptor and stimulates NFkappaB activity". FEBS Letters. 425 (3): 431–5. doi:10.1016/S0014-5793(98)00287-7. PMID 9563508.
Guan Z, Buckman SY, Pentland AP, Templeton DJ, Morrison AR (May 1998). "Induction of cyclooxygenase-2 by the activated MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway". The Journal of Biological Chemistry. 273 (21): 12901–8. doi:10.1074/jbc.273.21.12901. PMID 9582321.
Lee FS, Peters RT, Dang LC, Maniatis T (August 1998). "MEKK1 activates both IkappaB kinase alpha and IkappaB kinase beta". Proceedings of the National Academy of Sciences of the United States of America. 95 (16): 9319–24. doi:10.1073/pnas.95.16.9319. PMC 21336. PMID 9689078.
Yuasa T, Ohno S, Kehrl JH, Kyriakis JM (August 1998). "Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38". The Journal of Biological Chemistry. 273 (35): 22681–92. doi:10.1074/jbc.273.35.22681. PMID 9712898.
Pomérance M, Multon MC, Parker F, Venot C, Blondeau JP, Tocqué B, Schweighoffer F (September 1998). "Grb2 interaction with MEK-kinase 1 is involved in regulation of Jun-kinase activities in response to epidermal growth factor". The Journal of Biological Chemistry. 273 (38): 24301–4. doi:10.1074/jbc.273.38.24301. PMID 9733714.
Xia Y, Wu Z, Su B, Murray B, Karin M (November 1998). "JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extension". Genes & Development. 12 (21): 3369–81. doi:10.1101/gad.12.21.3369. PMC 317229. PMID 9808624.
Nemoto S, DiDonato JA, Lin A (December 1998). "Coordinate regulation of IkappaB kinases by mitogen-activated protein kinase kinase kinase 1 and NF-kappaB-inducing kinase". Molecular and Cellular Biology. 18 (12): 7336–43. doi:10.1128/mcb.18.12.7336. PMC 109315. PMID 9819420.
Yujiri T, Sather S, Fanger GR, Johnson GL (December 1998). "Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption". Science. 282 (5395): 1911–4. doi:10.1126/science.282.5395.1911. PMID 9836645.
Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M (May 1999). "Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain". Genes & Development. 13 (10): 1297–308. doi:10.1101/gad.13.10.1297. PMC 316725. PMID 10346818.
Kopp E, Medzhitov R, Carothers J, Xiao C, Douglas I, Janeway CA, Ghosh S (August 1999). "ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway". Genes & Development. 13 (16): 2059–71. doi:10.1101/gad.13.16.2059. PMC 316957. PMID 10465784.
Ito M, Yoshioka K, Akechi M, Yamashita S, Takamatsu N, Sugiyama K, Hibi M, Nakabeppu Y, Shiba T, Yamamoto KI (November 1999). "JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway". Molecular and Cellular Biology. 19 (11): 7539–48. doi:10.1128/mcb.19.11.7539. PMC 84763. PMID 10523642.
Minamino T, Yujiri T, Papst PJ, Chan ED, Johnson GL, Terada N (December 1999). "MEKK1 suppresses oxidative stress-induced apoptosis of embryonic stem cell-derived cardiac myocytes". Proceedings of the National Academy of Sciences of the United States of America. 96 (26): 15127–32. doi:10.1073/pnas.96.26.15127. PMC 24784. PMID 10611349.

[pmid8597633-1] Vinik BS, Kay ES, Fiedorek FT (November 1995). "Mapping of the MEK kinase gene (Mekk) to mouse chromosome 13 and human chromosome 5". Mammalian Genome. 6 (11): 782–3. doi:10.1007/BF00539003. PMID 8597633.

[entrez-2] 2.0 ^2.1 "Entrez Gene: MAP3K1 mitogen-activated protein kinase kinase kinase 1".

[Glubb_2015-3] Glubb DM, Maranian MJ, Michailidou K, Pooley KA, Meyer KB, Kar S, et al. (January 2015). "Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1". American Journal of Human Genetics. 96 (1): 5–20. doi:10.1016/j.ajhg.2014.11.009. PMC 4289692. PMID 25529635.

[pmid11884395-4] Zhang Y, Qiu WJ, Chan SC, Han J, He X, Lin SC (May 2002). "Casein kinase I and casein kinase II differentially regulate axin function in Wnt and JNK pathways". The Journal of Biological Chemistry. 277 (20): 17706–12. doi:10.1074/jbc.M111982200. PMID 11884395.

[pmid10829020-5] Zhang Y, Neo SY, Han J, Lin SC (August 2000). "Dimerization choices control the ability of axin and dishevelled to activate c-Jun N-terminal kinase/stress-activated protein kinase". The Journal of Biological Chemistry. 275 (32): 25008–14. doi:10.1074/jbc.M002491200. PMID 10829020.

[pmid10969079-6] 6.0 ^6.1 ^6.2 Karandikar M, Xu S, Cobb MH (December 2000). "MEKK1 binds raf-1 and the ERK2 cascade components". The Journal of Biological Chemistry. 275 (51): 40120–7. doi:10.1074/jbc.M005926200. PMID 10969079.

[pmid9733714-7] Pomérance M, Multon MC, Parker F, Venot C, Blondeau JP, Tocqué B, Schweighoffer F (September 1998). "Grb2 interaction with MEK-kinase 1 is involved in regulation of Jun-kinase activities in response to epidermal growth factor". The Journal of Biological Chemistry. 273 (38): 24301–4. doi:10.1074/jbc.273.38.24301. PMID 9733714.

[pmid9405400-8] Xu S, Cobb MH (December 1997). "MEKK1 binds directly to the c-Jun N-terminal kinases/stress-activated protein kinases". The Journal of Biological Chemistry. 272 (51): 32056–60. doi:10.1074/jbc.272.51.32056. PMID 9405400.

[pmid10346818-9] Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M (May 1999). "Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain". Genes & Development. 13 (10): 1297–308. doi:10.1101/gad.13.10.1297. PMC 316725. PMID 10346818.

[pmid9563508-10] Saltzman A, Searfoss G, Marcireau C, Stone M, Ressner R, Munro R, Franks C, D'Alonzo J, Tocque B, Jaye M, Ivashchenko Y (April 1998). "hUBC9 associates with MEKK1 and type I TNF-alpha receptor and stimulates NFkappaB activity". FEBS Letters. 425 (3): 431–5. doi:10.1016/s0014-5793(98)00287-7. PMID 9563508.

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v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list)

MAP3K1

Contents

Function

Interactions

References

Further reading

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