* 609487

MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 2; MAP3K2


Alternative titles; symbols

MAP/ERK KINASE KINASE 2; MEKK2


HGNC Approved Gene Symbol: MAP3K2

Cytogenetic location: 2q14.3     Genomic coordinates (GRCh38): 2:127,298,668-127,388,465 (from NCBI)


TEXT

Description

MEKK2 belongs to the mitogen-activated protein kinase (MAPK) kinase kinase gene family, which is involved in regulating multiple MAPK signaling pathways. MEKK2 is a major upstream activator of the JNK (see MAPK8; 601158) MAPK cascade (Guo et al., 2002).


Cloning and Expression

Blank et al. (1996) cloned mouse Mekk2. The 5-prime end of the cDNA is highly GC rich, and the deduced 619-amino acid protein contains a C-terminal catalytic domain with 11 conserved subdomains.

Raviv et al. (2004) found that endogenous MEKK2 localized mainly to the cytosol of unstimulated HeLa cells and rat fibroblasts.


Gene Function

By expression of mouse Mekk2 in human embryonic kidney cells, Blank et al. (1996) found that Mekk2 preferentially activated Jnk over p42 MAPK (MAPK1; 176948) or p44 MAPK (MAPK3; 601795). It did not activate p38 MAPK (MAPK14; 600289).

Garrington et al. (2000) found that Mekk2 was required for cytokine production in cultured mast cells derived from mouse embryonic stem cells. Transcription of cytokines in response to IgE (147180) or Kit (164920) was reduced in Mekk2-null mast cells relative to wildtype mast cells. Mutant mast cells also lost receptor-mediated stimulation of Jnk, but Jnk activation in response to ultraviolet irradiation was normal. Garrington et al. (2000) concluded that MEKK2 is required for receptor signaling, but not for cellular stress responses.

Raviv et al. (2004) found that endogenous HeLa cell and rat fibroblast MEKK2 translocated to the nucleus upon mitogenic stimulation, where it activated nuclear ERK5 (MAPK7; 602521) and MEK5 (MAP2K5; 602520).

By RT-PCR of rheumatoid arthritis and osteoarthritis synovial tissues, Hammaker et al. (2004) detected high MEKK1 (MAP3K1; 600982), MEKK2, ASK1 (MAP3K5; 602448), and TAK1 (MAP3K7; 602614) expression, but only trace amounts of other MAPKs. Hammaker et al. (2004) immunoprecipitated MEKK2 from cultured human fibroblast-like synoviocytes and demonstrated that IL1 (see 147760) increased MEKK2-mediated in vitro phosphorylation of MKK4 (MAP2K4; 601335) and MKK7 (MAP2K7; 603014), which are key MAPKs that activate JNK. Furthermore, MEKK2 immunoprecipitates activated JUN (165160) in an IL1-dependent manner. Hammaker et al. (2004) concluded that MEKK2 is an important activator of the JNK pathway in arthritis.

Pelkmans and Zerial (2005) used RNAi to explore the role of kinases in caveolae dynamics and identified MAP3K2 as 1 of 6 kinases that regulate different steps of the caveolar cycle. Silencing of MAP3K2 strongly reduced kiss-and-run dynamics, leading to an accumulation of caveolar structures at the cell surface without affecting caveolae coat assembly or clustering. Their observations revealed new principles in caveolae trafficking and suggested that the dynamic properties of caveolae and their transport competence are regulated by different kinases operating at several levels.

Mazur et al. (2014) demonstrated that methylation of MAP3K2 by SMYD3 (608783) increases MAP kinase signaling and promotes the formation of Ras-driven carcinomas. Using mouse models for pancreatic ductal adenocarcinoma and lung adenocarcinoma, Mazur et al. (2014) found that abrogating Smyd3 catalytic activity inhibits tumor development in response to oncogenic Ras (see 190070). The authors used protein array technology to identify MAP3K2 as a target of SMYD3. In cancer cell lines, SMYD3-mediated methylation of MAP3K2 at lys260 potentiates activation of the Ras/Raf/MEK/ERK signaling module, and SMYD3 depletion synergizes with a MEK inhibitor to block Ras-driven tumorigenesis. Finally, the PP2A phosphatase complex, a key negative regulator of the MAP kinase pathway, binds to MAP3K2, and this interaction is blocked by methylation. Mazur et al. (2014) concluded that their results elucidated a role for lysine methylation in integrating cytoplasmic kinase-signaling cascades, and established a pivotal role for SMYD3 in the regulation of oncogenic Ras signaling.


Mapping

The International Radiation Hybrid Mapping Consortium mapped the MAP3K2 gene to chromosome 2 (SHGC-56784).


Animal Model

Guo et al. (2002) found that Mekk2-null mice were viable and fertile. Major subsets of Mekk2-null thymic and splenic T cells were indistinguishable from those in wildtype mice. However, Mekk2-null T-cell proliferation was increased in response to anti-CD3 (see 186740) monoclonal antibody stimulation, and these T cells produced more IL2 (147680) and gamma-interferon (IFNG; 147570) than did wildtype T cells. Mekk2-null thymocytes were more susceptible than wildtype thymocytes to anti-CD3 antibody-induced cell death. However, rather than being depressed, T-cell receptor-mediated Jnk activation was moderately enhanced in Mekk2-null T cells. Guo et al. (2002) concluded that MEKK2 may be required for controlling the strength of T-cell receptor/CD3 signaling.


REFERENCES

  1. Blank, J. L., Gerwins, P., Elliott, E. M., Sather, S., Johnson, G. L. Molecular cloning of mitogen-activated protein/ERK kinase kinases (MEKK) 2 and 3: regulation of sequential phosphorylation pathways involving mitogen-activated protein kinase and c-Jun kinase. J. Biol. Chem. 271: 5361-5368, 1996. [PubMed: 8621389, related citations] [Full Text]

  2. Garrington, T. P., Ishizuka, T., Papst, P. J., Chayama, K., Webb, S., Yujiri, T., Sun, W., Sather, S., Russell, D. M., Gibson, S. B., Keller, G., Gelfand, E. W., Johnson, G. L. MEKK2 gene disruption causes loss of cytokine production in response to IgE and c-Kit ligand stimulation of ES cell-derived mast cells. EMBO J. 19: 5387-5395, 2000. [PubMed: 11032806, images, related citations] [Full Text]

  3. Guo, Z., Clydesdale, G., Cheng, J., Kim, K., Gan, L., McConkey, D. J., Ullrich, S. E., Zhuang, Y., Su, B. Disruption of Mekk2 in mice reveals an unexpected role for MEKK2 in modulating T-cell receptor signal transduction. Molec. Cell. Biol. 22: 5761-5768, 2002. [PubMed: 12138187, images, related citations] [Full Text]

  4. Hammaker, D. R., Boyle, D. L., Chabaud-Riou, M., Firestein, G. S. Regulation of c-Jun N-terminal kinase by MEKK-2 and mitogen-activated protein kinase kinase kinases in rheumatoid arthritis. J. Immun. 172: 1612-1618, 2004. [PubMed: 14734742, related citations] [Full Text]

  5. Mazur, P. K., Reynoird, N., Khatri, P., Jansen, P. W. T. C., Wilkinson, A. W., Liu, S., Barbash, O., Van Aller, G. S., Huddleston, M., Dhanak, D., Tummino, P. J., Kruger, R. G., Garcia, B. A., Butte, A. J., Vermeulen, M., Sage, J., Gozani, O. SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 510: 283-287, 2014. [PubMed: 24847881, images, related citations] [Full Text]

  6. Pelkmans, L., Zerial, M. Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae. Nature 436: 128-133, 2005. [PubMed: 16001074, related citations] [Full Text]

  7. Raviv, Z., Kalie, E., Seger, R. MEK5 and ERK5 are localized in the nuclei of resting as well as stimulated cells, while MEKK2 translocates from the cytosol to the nucleus upon stimulation. J. Cell Sci. 117: 1773-1784, 2004. [PubMed: 15075238, related citations] [Full Text]


Ada Hamosh - updated : 07/17/2014
Ada Hamosh - updated : 8/3/2005
Creation Date:
Patricia A. Hartz : 7/21/2005
alopez : 07/17/2014
alopez : 8/4/2005
terry : 8/3/2005
mgross : 7/21/2005

* 609487

MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 2; MAP3K2


Alternative titles; symbols

MAP/ERK KINASE KINASE 2; MEKK2


HGNC Approved Gene Symbol: MAP3K2

Cytogenetic location: 2q14.3     Genomic coordinates (GRCh38): 2:127,298,668-127,388,465 (from NCBI)


TEXT

Description

MEKK2 belongs to the mitogen-activated protein kinase (MAPK) kinase kinase gene family, which is involved in regulating multiple MAPK signaling pathways. MEKK2 is a major upstream activator of the JNK (see MAPK8; 601158) MAPK cascade (Guo et al., 2002).


Cloning and Expression

Blank et al. (1996) cloned mouse Mekk2. The 5-prime end of the cDNA is highly GC rich, and the deduced 619-amino acid protein contains a C-terminal catalytic domain with 11 conserved subdomains.

Raviv et al. (2004) found that endogenous MEKK2 localized mainly to the cytosol of unstimulated HeLa cells and rat fibroblasts.


Gene Function

By expression of mouse Mekk2 in human embryonic kidney cells, Blank et al. (1996) found that Mekk2 preferentially activated Jnk over p42 MAPK (MAPK1; 176948) or p44 MAPK (MAPK3; 601795). It did not activate p38 MAPK (MAPK14; 600289).

Garrington et al. (2000) found that Mekk2 was required for cytokine production in cultured mast cells derived from mouse embryonic stem cells. Transcription of cytokines in response to IgE (147180) or Kit (164920) was reduced in Mekk2-null mast cells relative to wildtype mast cells. Mutant mast cells also lost receptor-mediated stimulation of Jnk, but Jnk activation in response to ultraviolet irradiation was normal. Garrington et al. (2000) concluded that MEKK2 is required for receptor signaling, but not for cellular stress responses.

Raviv et al. (2004) found that endogenous HeLa cell and rat fibroblast MEKK2 translocated to the nucleus upon mitogenic stimulation, where it activated nuclear ERK5 (MAPK7; 602521) and MEK5 (MAP2K5; 602520).

By RT-PCR of rheumatoid arthritis and osteoarthritis synovial tissues, Hammaker et al. (2004) detected high MEKK1 (MAP3K1; 600982), MEKK2, ASK1 (MAP3K5; 602448), and TAK1 (MAP3K7; 602614) expression, but only trace amounts of other MAPKs. Hammaker et al. (2004) immunoprecipitated MEKK2 from cultured human fibroblast-like synoviocytes and demonstrated that IL1 (see 147760) increased MEKK2-mediated in vitro phosphorylation of MKK4 (MAP2K4; 601335) and MKK7 (MAP2K7; 603014), which are key MAPKs that activate JNK. Furthermore, MEKK2 immunoprecipitates activated JUN (165160) in an IL1-dependent manner. Hammaker et al. (2004) concluded that MEKK2 is an important activator of the JNK pathway in arthritis.

Pelkmans and Zerial (2005) used RNAi to explore the role of kinases in caveolae dynamics and identified MAP3K2 as 1 of 6 kinases that regulate different steps of the caveolar cycle. Silencing of MAP3K2 strongly reduced kiss-and-run dynamics, leading to an accumulation of caveolar structures at the cell surface without affecting caveolae coat assembly or clustering. Their observations revealed new principles in caveolae trafficking and suggested that the dynamic properties of caveolae and their transport competence are regulated by different kinases operating at several levels.

Mazur et al. (2014) demonstrated that methylation of MAP3K2 by SMYD3 (608783) increases MAP kinase signaling and promotes the formation of Ras-driven carcinomas. Using mouse models for pancreatic ductal adenocarcinoma and lung adenocarcinoma, Mazur et al. (2014) found that abrogating Smyd3 catalytic activity inhibits tumor development in response to oncogenic Ras (see 190070). The authors used protein array technology to identify MAP3K2 as a target of SMYD3. In cancer cell lines, SMYD3-mediated methylation of MAP3K2 at lys260 potentiates activation of the Ras/Raf/MEK/ERK signaling module, and SMYD3 depletion synergizes with a MEK inhibitor to block Ras-driven tumorigenesis. Finally, the PP2A phosphatase complex, a key negative regulator of the MAP kinase pathway, binds to MAP3K2, and this interaction is blocked by methylation. Mazur et al. (2014) concluded that their results elucidated a role for lysine methylation in integrating cytoplasmic kinase-signaling cascades, and established a pivotal role for SMYD3 in the regulation of oncogenic Ras signaling.


Mapping

The International Radiation Hybrid Mapping Consortium mapped the MAP3K2 gene to chromosome 2 (SHGC-56784).


Animal Model

Guo et al. (2002) found that Mekk2-null mice were viable and fertile. Major subsets of Mekk2-null thymic and splenic T cells were indistinguishable from those in wildtype mice. However, Mekk2-null T-cell proliferation was increased in response to anti-CD3 (see 186740) monoclonal antibody stimulation, and these T cells produced more IL2 (147680) and gamma-interferon (IFNG; 147570) than did wildtype T cells. Mekk2-null thymocytes were more susceptible than wildtype thymocytes to anti-CD3 antibody-induced cell death. However, rather than being depressed, T-cell receptor-mediated Jnk activation was moderately enhanced in Mekk2-null T cells. Guo et al. (2002) concluded that MEKK2 may be required for controlling the strength of T-cell receptor/CD3 signaling.


REFERENCES

  1. Blank, J. L., Gerwins, P., Elliott, E. M., Sather, S., Johnson, G. L. Molecular cloning of mitogen-activated protein/ERK kinase kinases (MEKK) 2 and 3: regulation of sequential phosphorylation pathways involving mitogen-activated protein kinase and c-Jun kinase. J. Biol. Chem. 271: 5361-5368, 1996. [PubMed: 8621389] [Full Text: https://doi.org/10.1074/jbc.271.10.5361]

  2. Garrington, T. P., Ishizuka, T., Papst, P. J., Chayama, K., Webb, S., Yujiri, T., Sun, W., Sather, S., Russell, D. M., Gibson, S. B., Keller, G., Gelfand, E. W., Johnson, G. L. MEKK2 gene disruption causes loss of cytokine production in response to IgE and c-Kit ligand stimulation of ES cell-derived mast cells. EMBO J. 19: 5387-5395, 2000. [PubMed: 11032806] [Full Text: https://doi.org/10.1093/emboj/19.20.5387]

  3. Guo, Z., Clydesdale, G., Cheng, J., Kim, K., Gan, L., McConkey, D. J., Ullrich, S. E., Zhuang, Y., Su, B. Disruption of Mekk2 in mice reveals an unexpected role for MEKK2 in modulating T-cell receptor signal transduction. Molec. Cell. Biol. 22: 5761-5768, 2002. [PubMed: 12138187] [Full Text: https://doi.org/10.1128/MCB.22.16.5761-5768.2002]

  4. Hammaker, D. R., Boyle, D. L., Chabaud-Riou, M., Firestein, G. S. Regulation of c-Jun N-terminal kinase by MEKK-2 and mitogen-activated protein kinase kinase kinases in rheumatoid arthritis. J. Immun. 172: 1612-1618, 2004. [PubMed: 14734742] [Full Text: https://doi.org/10.4049/jimmunol.172.3.1612]

  5. Mazur, P. K., Reynoird, N., Khatri, P., Jansen, P. W. T. C., Wilkinson, A. W., Liu, S., Barbash, O., Van Aller, G. S., Huddleston, M., Dhanak, D., Tummino, P. J., Kruger, R. G., Garcia, B. A., Butte, A. J., Vermeulen, M., Sage, J., Gozani, O. SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 510: 283-287, 2014. [PubMed: 24847881] [Full Text: https://doi.org/10.1038/nature13320]

  6. Pelkmans, L., Zerial, M. Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae. Nature 436: 128-133, 2005. [PubMed: 16001074] [Full Text: https://doi.org/10.1038/nature03866]

  7. Raviv, Z., Kalie, E., Seger, R. MEK5 and ERK5 are localized in the nuclei of resting as well as stimulated cells, while MEKK2 translocates from the cytosol to the nucleus upon stimulation. J. Cell Sci. 117: 1773-1784, 2004. [PubMed: 15075238] [Full Text: https://doi.org/10.1242/jcs.01040]


Contributors:
Ada Hamosh - updated : 07/17/2014
Ada Hamosh - updated : 8/3/2005

Creation Date:
Patricia A. Hartz : 7/21/2005

Edit History:
alopez : 07/17/2014
alopez : 8/4/2005
terry : 8/3/2005
mgross : 7/21/2005