MAP3K3

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Mitogen-activated protein kinase kinase kinase 3
Protein MAP3K3 PDB 2c60.png
PDB rendering based on 2c60.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols MAP3K3 ; MAPKKK3; MEKK3
External IDs OMIM602539 MGI1346874 HomoloGene69110 IUPHAR: 2078 ChEMBL: 5970 GeneCards: MAP3K3 Gene
EC number 2.7.11.25
RNA expression pattern
PBB GE MAP3K3 203514 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4215 26406
Ensembl ENSG00000198909 ENSMUSG00000020700
UniProt Q99759 Q61084
RefSeq (mRNA) NM_002401 NM_011947
RefSeq (protein) NP_002392 NP_036077
Location (UCSC) Chr 17:
63.62 – 63.7 Mb
Chr 11:
106.08 – 106.16 Mb
PubMed search [1] [2]

Mitogen-activated protein kinase kinase kinase 3 is an enzyme that in humans is encoded by the MAP3K3 gene,[1] which is located on the long arm of chromosome 17 (17q23.3).[2]

This gene product is a 626-amino acid polypeptide that is 96.5% identical to mouse MEKK3. Its catalytic domain is closely related to those of several other kinases, including mouse MEKK2, tobacco NPK, and yeast STE11. Northern blot analysis revealed a 4.6-kb transcript that appears to be ubiquitously expressed.

MAP3Ks are involved in regulating cell fate in response to external stimuli.[3] MAP3K3 directly regulates the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively. In cotransfection assays, it enhanced transcription from a nuclear factor kappa-B (NFKB)-dependent reporter gene, consistent with a role in the SAPK pathway. Alternatively spliced transcript variants encoding distinct isoforms have been observed.[4] MEKK3 regulates the p38, JNK and ERK1/2 pathways.[3]

Interactions[edit]

MAP3K3 has been shown to interact with [SQSTM1/p62], MAP2K5,[5][6] YWHAE,[7] GAB1,[8] BRCA1,[9] and AKT.[10]

MAP3K3 in cancer[edit]

Many studies have described the association of MAP3K3 (or MEKK3) in cancer.

Two SNPs in the MAP3K3 gene were found as candidates for association with colon and rectal cancers.[11]

MEKK3 is highly expressed in 4 ovarian cancer cell lines (OVCA429, Hey, DOV13, and SKOv3). This expression level is significantly higher in those cancer cells when compared to normal cells. MEKK3 expression levels are comparable to IKK kinase activities, which also relate to activation of NFκB. High expression of MEKK3 in most of these ovarian cancer cells supposedly activate IKK kinase activity, which lead to increased levels of active NFκB. Also, MEKK3 interacts with AKT to activate NFκB. Genes related to cell survival and anti-apoptosis have increased expression in most cancer cells with high levels of MEKK3. This is probably due to constitutive activation of NFκB, which will regulate those genes. In this sense, knockdown of MEKK3 caused ovarian cancer cells to be more sensitive to drugs.[10]

MEKK3 also interacts with BRCA1. Knocking down BRCA1 resulted in inhibited MEKK3 kinase activity. The drug paclitaxel induces MEKK3 activity and it requires functional BRCA1 to do it. It was observed that in a breast cancer cell line BRCA1-deficient (HCC1937), paclitaxel was unable to activate MEKK3. Paclitaxel may be inducing stress-response through the MEKK3/JNK/p38/MAPK pathway, but not in mutated BRCA1 cells.[9]

Normal endothelial cells, but deficient in MEKK3, have reduced cell proliferation and increased apoptosis. MEKK3-deficient tumors, on the other hand, can grow in the same rate as regular tumors, also producing comparable levels of VEGF and inducing angiogenesis comparably to wild-type tumors. While these results show that MEKK3 is important for normal endothelial cells, MEKK3 may not be necessary for tumor growth and angiogenesis.[12]

MEKK3 expression level is also significantly higher in cervical cancer in comparison with chronic cervicitis and CIN (cervical intraepithelial neoplasia). This high expression correlates with the also high levels of survivin (apoptosis inhibitor), and they both may associate with cervical cancer development and prognosis.[13] Cao et al. suggest a targeted therapy of MEKK3 together with a therapy that promotes apoptosis as a possible new strategy for treatment of chemotherapeutic-resistant tumors.

Similarly, significantly higher levels of MEKK3 was found as well in esophageal dysplasia and esophageal squamous cell carcinoma (ESCC) when compared to normal esophageal tissue. MEKK3 seems to accumulate even more in ESCC than esophageal dysplasia, which also correlates with poor prognosis of ESCC. Therefore, MEKK3 can be studied for its possible role as an early biomarker of esophageal tumorigenesis.[14]

From all these studies, MEKK3 has become a valuable target for the development of new cancer therapies and diagnosis/prognosis tools.

References[edit]

  1. ^ Ellinger-Ziegelbauer H, Brown K, Kelly K, Siebenlist U (March 1997). "Direct activation of the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by an inducible mitogen-activated protein Kinase/ERK kinase kinase 3 (MEKK) derivative". J Biol Chem 272 (5): 2668–74. doi:10.1074/jbc.272.5.2668. PMID 9006902. 
  2. ^ MAP3K3 in GeneCards - The Human Gene Compendium. http://www.genecards.org/cgi-bin/carddisp.pl?gene=MAP3K3
  3. ^ a b Craig EA, Stevens MV, Vaillancourt RR, et al (2008). MAP3Ks as central regulators of cell fate during development. Developmental Dynamics, 237, 3102-14.
  4. ^ "Entrez Gene: MAP3K3 mitogen-activated protein kinase kinase kinase 3". 
  5. ^ Sun, W; Kesavan K; Schaefer B C; Garrington T P; Ware M; Johnson N L; Gelfand E W; Johnson G L (February 2001). "MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway". J. Biol. Chem. (United States) 276 (7): 5093–100. doi:10.1074/jbc.M003719200. ISSN 0021-9258. PMID 11073940. 
  6. ^ Bouwmeester, Tewis; Bauch Angela, Ruffner Heinz, Angrand Pierre-Olivier, Bergamini Giovanna, Croughton Karen, Cruciat Cristina, Eberhard Dirk, Gagneur Julien, Ghidelli Sonja, Hopf Carsten, Huhse Bettina, Mangano Raffaella, Michon Anne-Marie, Schirle Markus, Schlegl Judith, Schwab Markus, Stein Martin A, Bauer Andreas, Casari Georg, Drewes Gerard, Gavin Anne-Claude, Jackson David B, Joberty Gerard, Neubauer Gitte, Rick Jens, Kuster Bernhard, Superti-Furga Giulio (February 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nat. Cell Biol. (England) 6 (2): 97–105. doi:10.1038/ncb1086. ISSN 1465-7392. PMID 14743216. 
  7. ^ Fanger, G R; Widmann C; Porter A C; Sather S; Johnson G L; Vaillancourt R R (February 1998). "14-3-3 proteins interact with specific MEK kinases". J. Biol. Chem. (UNITED STATES) 273 (6): 3476–83. doi:10.1074/jbc.273.6.3476. ISSN 0021-9258. PMID 9452471. 
  8. ^ Che, Wenyi; Lerner-Marmarosh Nicole, Huang Qunhua, Osawa Masaki, Ohta Shinsuke, Yoshizumi Masanori, Glassman Michael, Lee Jiing-Dwan, Yan Chen, Berk Bradford C, Abe Jun-Ichi (June 2002). "Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-alpha-induced c-Jun and NF-kappaB activation and adhesion molecule expression". Circ. Res. (United States) 90 (11): 1222–30. doi:10.1161/01.RES.0000021127.83364.7D. PMID 12065326. 
  9. ^ a b Gilmore, Paula M; McCabe Nuala, Quinn Jennifer E, Kennedy Richard D, Gorski Julia J, Andrews Heather N, McWilliams Stewart, Carty Michael, Mullan Paul B, Duprex W Paul, Liu Edison T, Johnston Patrick G, Harkin D Paul (June 2004). "BRCA1 interacts with and is required for paclitaxel-induced activation of mitogen-activated protein kinase kinase kinase 3". Cancer Res. (United States) 64 (12): 4148–54. doi:10.1158/0008-5472.CAN-03-4080. ISSN 0008-5472. PMID 15205325. 
  10. ^ a b Samanta AK, Huang HJ, Le XF, et al (2009). MEKK3 expression correlates with nuclear factor kappa B activity and with expression of anti-apoptotic genes in serous ovarian carcinoma. Cancer, 115, 3897-908.
  11. ^ Slattery ML, Lundgreen A, Wolff RK (2012). MAP kinase genes and colon and rectal cancer. Carcinogenesis, 33(12), 2398-408.
  12. ^ Deng Y, Yang J, McCarty M, et al (2007). MEKK3 is required for endothelium function but is not essential for tumor growth and angiogenesis. Am J Physiol Cell Physiol, 293, 1404-11.
  13. ^ Cao XQ, Lu HS, Zhang L, Chen LL, Gan MF (2014). MEKK3 and survivin expression in cervical cancer: association with clinicopathological factors and prognosis. Asian Pac J Cancer Prev., 15(13), 5271-6
  14. ^ Hasan R, Sharma R, Saraya A, et al (2014). Mitogen activated protein kinase kinase kinase 3 (MAP3K3/MEKK3) overexpression is an early event in esophageal tumorigenesis and is a predictor of poor disease prognosis. BMC Cancer, 14, 2.

Further reading[edit]