* 600982

MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 1; MAP3K1


Alternative titles; symbols

MAP/ERK KINASE KINASE 1; MEKK1
MAPKKK1
MEK KINASE


HGNC Approved Gene Symbol: MAP3K1

Cytogenetic location: 5q11.2     Genomic coordinates (GRCh38): 5:56,815,549-56,896,152 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
5q11.2 46XY sex reversal 6 613762 AD 3

TEXT

Description

MAP3K1, or MEKK1, is a mitogen-activated protein kinase (MAPK) kinase kinase that regulates the ERK (see 601795) and JNK (see 601158) MAPK pathways, as well as the transcription factor NF-kappa-B (see 164011) and the transcriptional coactivator p300 (EP300; 602700). MAP3K1 generates antiapoptotic signaling as a full-length protein, but it induces apoptosis following cleavage by caspases (see 147678) (summary by Schlesinger et al., 2002).


Cloning and Expression

Xia et al. (1998) cloned human MEKK1 from HeLa, B-cell, and Jurkat cDNA libraries. The deduced 1,495-amino acid protein has a C-terminal catalytic domain and shares 83% identity with rat Mekk1. Western blot analysis detected MEKK1 at an apparent molecular mass of 200 kD in transfected COS-1 cells.

Xu et al. (1996) cloned rat Mekk1. The deduced 1,493-amino acid rat Mekk1 protein contains 2 N-terminal proline-rich domains, followed by a cysteine-rich region, 2 pleckstrin (PLEK; 173570) homology (PH) domains, and a C-terminal kinase domain. Western blot analysis detected endogenous MEKK1 at an apparent molecular mass of about 195 kD in human 293 cells. Mekk1 proteins with similar molecular masses were detected in mouse, rat, and Chinese hamster cell lines. Fractionation of cells expressing rat Mekk1 revealed that the full-length protein associated with membranes. A Mekk1 C-terminal catalytic domain fragment associated with both the soluble fraction and with membranes.

Pearlman et al. (2010) demonstrated high levels of expression of Map3k1 in mouse gonads within 13.5 days postcoitum (dpc), with approximately equal expression in male and female gonads. Map3k1 expression was also observed throughout the mouse embryonic gonad at 11.5 dpc, the sex-determining stage of gonad development. Staining occurred within the testis cords at 13.5 dpc in a pattern indicative of Sertoli cell expression.


Gene Structure

Pearlman et al. (2010) noted that the MAP3K1 gene contains 20 exons.


Mapping

Vinik et al. (1995) identified DNA sequence and size polymorphisms in intronic and 3-prime untranslated regions of the mouse Map3k1 gene and the human MAP3K1 homolog. Using these allele-specific polymorphisms, they mapped the Map3k1 gene in an intersubspecific backcross to mouse chromosome 13. They mapped the human MAP3K1 gene to chromosome 5 by somatic cell hybrid analysis.


Gene Function

By assaying transfected COS-1 cells, Xia et al. (1998) showed that human MEKK1 activated JNK1 (MAPK8; 601158) robustly and p38-alpha (MAPK14; 600289) less efficiently, but it had only a marginal effect on ERK2 (MAPK1; 176948). MEKK1 directly and specifically interacted with JNKK1 (MAP2K4; 601335) and activated JNKK1 in cells and in vitro. Phosphorylation of JNKK1 by MEKK1 disrupted their interaction. MEKK1 and JNK1 competed for binding to JNKK1. Xia et al. (1998) concluded that JNKK1 is the preferred MEKK1 substrate.

Gamma-interferon (IFNG; 147570) induces a number of genes, including MEKK1, to upregulate cellular responses by using specific transcription factors and the cognate elements (Roy et al., 2002).

Lu et al. (2002) found that the PHD domain of MEKK1, a RING finger-like structure, exhibited E3 ubiquitin ligase activity toward ERK2 in vitro and in vivo. Moreover, both MEKK1 kinase activity and the docking motif on ERK1 (601795)/ERK2 were involved in ERK1/ERK2 ubiquitination. Significantly, cells expressing ERK2 with the docking motif mutation were resistant to sorbitol-induced apoptosis. Therefore, MEKK1 functions not only as an upstream activator of ERK and JNK through its kinase domain, but also as an E3 ligase through its PHD domain, providing a negative regulatory mechanism for decreasing ERK1/ERK2 activity.

Schlesinger et al. (2002) stated that full-length mouse Mekk1 generates antiapoptotic signals, while a 91-kD C-terminal Mekk1 fragment induces apoptosis. They found that caspase-dependent cleavage of Mekk1 relocalized the 91-kD fragment from the particulate fraction to a soluble cytoplasmic fraction. Schlesinger et al. (2002) concluded that MEKK1 functions as a molecular switch to regulate apoptosis in a caspase-dependent manner.

Cytokine signaling is thought to require assembly of multicomponent signaling complexes at cytoplasmic segments of membrane-embedded receptors, in which receptor-proximal protein kinases are activated. Matsuzawa et al. (2008) reported that, upon ligation, CD40 (109535) formed a complex containing adaptor molecules TRAF2 (601895) and TRAF3 (601896), ubiquitin-conjugating enzyme UBC13 (UBE2N; 603679), cellular inhibitor of apoptosis protein-1 (CIAP1, or BIRC2; 601712) and -2 (CIAP2, or BIRC3; 601721), IKK-gamma (IKBKG; 300248), and MEKK1. TRAF2, UBC13, and IKK-gamma were required for complex assembly and activation of MEKK1 and MAP kinase cascades. However, the kinases were not activated unless the complex was translocated from the membrane to the cytosol upon CIAP1/CIAP2-induced degradation of TRAF3. Matsuzawa et al. (2008) proposed that this 2-stage signaling mechanism may apply to other innate immune receptors and may account for spatial and temporal separation of MAPK and IKK signaling.


Molecular Genetics

Association with Breast Cancer

Easton et al. (2007) identified an A/C SNP (rs889312) in the MAP3K1 gene that was significantly (p = 7 x 10(-20)) associated with familial breast cancer (114480) in a 3-stage genomewide association study of 22,848 cases from 22 studies. Easton et al. (2007) found that the allele was common in the U.K. population and thus unlikely to confer increased disease risk individually. However, in combination with other susceptibility alleles, the SNP may become clinically significant.

In a sample of 10,358 carriers of BRCA1 (113705) or BRCA2 (600185) gene mutations from 23 studies, Antoniou et al. (2008) did not observe an overall association between rs889312 and increased risk of breast cancer. However, when the group was stratified, BRCA2 mutation carriers who also carried the minor allele of the SNP were at slightly increased risk (hazard ratio of 1.12; p(trend) = 0.02). The authors concluded that this locus interacts multiplicatively on breast cancer risk in BRCA2 mutation carriers.

46,XY Sex Reversal 6

In a French family with 46,XY gonadal dysgenesis mapping to chromosome 5q (SRXY6; 613762), Pearlman et al. (2010) analyzed the MAP3K1 gene and identified a heterozygous splice site mutation that segregated with disease in the family (600982.0001). Sequence analysis of MAP3K1 in a New Zealand family with 46,XY gonadal dysgenesis identified a missense mutation (600982.0002). Screening of MAP3K1 in 11 sporadic cases revealed 2 more missense mutations in 2 patients (600982.0003 and 600982.0004, respectively). In cultured primary lymphoblastoid cells from the French family and 2 sporadic patients, the mutations were found to alter phosphorylation of the downstream targets p38 (MAPK14; 600289) and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) and to enhance binding of RHOA (165390) to the MAP3K1 complex.

Using human B-cell lymphoblastoid cell lines and NT2/D1 human teratocarcinoma cells, Loke et al. (2014) found that MAP3K1 splicing and missense mutations associated with gonadal dysgenesis increased phosphorylation of p38 and ERK1/ERK2 and binding of RHOA, MAP3K4 (602425), FRAT1 (602503), and AXIN1 (603816). Overexpression of RHOA or reducing expression of MAP3K4 phenocopied the MAP3K1 mutations in NT2/D1 cells. The effects of the MAP3K1 mutations were rescued by cotransfection with wildtype MAP3K4. Loke et al. (2014) concluded that, although MAP3K1 is not usually required for testis determination, MAP3K1 mutations can disrupt normal development through gains of function.

In 7 46,XY females with complete or partial gonadal dysgenesis from 4 unrelated families, Granados et al. (2017) identified heterozygosity for mutations in the MAP3K1 gene (see, e.g., 600982.0005 and 600982.0006).

Using structural modeling and functional data, Chamberlin et al. (2019) examined MAP3K1 mutations associated with 46,XY gonadal dysgenesis. These pathogenic mutations clustered in the guanine exchange factor (GEF), plant homeodomain (PHD), and armadillo repeat (ARM) domains and disrupted their structures, resulting in overactivation of MAP3K1 kinase signaling and disruption of the testis development pathway.


Animal Model

Yujiri et al. (1998) targeted disruption of the gene encoding Mekk1 to define its function in the regulation of MAP kinase pathways and cell survival. Mekk1 -/- embryonic stem cells from mice had lost or altered responses of Jnk to microtubule disruption and cold stress but activated Jnk normally in response to heat shock, anisomycin, and ultraviolet irradiation. Activation of Jnk was lost and that of Erk was diminished in response to hyperosmolarity and serum factors in Mekk1 -/- cells. Loss of Mekk1 expression resulted in a greater apoptotic response of cells to hyperosmolarity and microtubule disruption. When activated by specific stresses that alter cell shape and the cytoskeleton, Mekk1 signals to protect cells from apoptosis.

Minamino et al. (1999) found that Mekk1 -/- mouse embryonic stem cell-derived cardiac myocytes were extremely sensitive to hydrogen peroxide-induced apoptosis. Elevated sensitivity was due to enhanced Tnf-alpha (TNF; 191160) production, which was negatively regulated by the Mekk1-Jnk pathway in wildtype mice.

The BALB/cGa mouse strain and its descendants produced 2 waves of high frequency of spontaneous heritable mutations. Juriloff et al. (2005) determined that one of these mutations, referred to as ophthalmatrophy (oa) or lidgap-Gates (lg-Ga), is a 27.5-kb deletion of exons 2 to 9 of the Map3k1 gene. The mutation causes a failure of fetal eyelid development, resulting in the defect 'open eyelids at birth.' Affected eyes develop corneal opacity by adulthood.


ALLELIC VARIANTS ( 6 Selected Examples):

.0001 46,XY SEX REVERSAL 6

MAP3K1, IVS2AS, T-A, -8
  
RCV000023055

In 5 affected individuals from a large multigenerational French family with 46,XY gonadal dysgenesis, complete or partial (SRXY6; 613762), originally reported by Le Caignec et al. (2003), Pearlman et al. (2010) identified heterozygosity for a splice acceptor site mutation (634-8T-A) in intron 2 of MAP3K1, resulting in the insertion of 2 amino acids in-frame at this site. Two mutation-positive individuals were phenotypic females who on laparotomy had right-sided streak gonads and left-sided dysgenetic testes, with a dysgerminoma of the right streak gonad in one patient and a dysgerminoma and gonadoblastoma of the left dysgenetic testis in the other patient. The other 3 mutation-positive family members were phenotypic males, 1 with penile hypospadias and chordee, and the 2 other with perineal hypospadias, 1 of whom also had chordee. The ratio of mutant to wildtype transcript was greater than 1 in lymphoblastoid cells from affected individuals. The mutation was not found in 100 unrelated French controls of European descent or in the 1000 Genomes Project. In cultured primary lymphoblastoid cells, the mutation was found to increase phosphorylation of the downstream targets p38 (MAPK14; 600289) and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) compared to wildtype; coimmunoprecipitation studies demonstrated enhanced binding of RHOA (165390) to the mutant MAP3K1 complex.


.0002 46,XY SEX REVERSAL 6

MAP3K1, GLY616ARG
  
RCV000023056...

In affected individuals from a 3-generation New Zealand family of European descent with 46,XY gonadal dysgenesis, complete or partial (SRXY6; 613762), originally reported by Espiner et al. (1970), Pearlman et al. (2010) identified heterozygosity for a 1846G-A transition in exon 10 of the MAP3K1 gene, resulting in a gly616-to-arg (G616R) substitution. The mutation was not found in 100 unrelated ethnically matched controls or in the 1000 Genomes Project. A patient cell line from this family was not available for analysis.


.0003 46,XY SEX REVERSAL 6

MAP3K1, LEU189PRO
  
RCV000023057...

In a sporadic patient with 46,XY complete gonadal dysgenesis (SRXY6; 613762), Pearlman et al. (2010) identified heterozygosity for a 566T-C transition in exon 2 of the MAP3K1 gene, resulting in a leu189-to-pro (L189P) substitution within the phylogenetically conserved focal adhesion kinase (FAK) binding site. The mutation was not found in 100 unrelated ethnically matched controls or in the 1000 Genomes Project. In cultured primary lymphoblastoid cells, the mutation was found to increase phosphorylation of the downstream target ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) compared to wildtype, and coimmunoprecipitation studies demonstrated enhanced binding of RHOA (165390) to the mutant MAP3K1 complex.


.0004 46,XY SEX REVERSAL 6

MAP3K1, LEU189ARG
  
RCV000023058

In a sporadic patient with 46,XY complete gonadal dysgenesis (613762), Pearlman et al. (2010) identified heterozygosity for a 566T-G transversion in exon 2 of the MAP3K1 gene, resulting in a leu189-to-arg (L189R) substitution within the phylogenetically conserved focal adhesion kinase (FAK) binding site. The mutation was not found in 100 unrelated ethnically matched controls or in the 1000 Genomes Project. In cultured primary lymphoblastoid cells, the mutation was found to increase phosphorylation of the downstream targets p38 (MAPK14; 600289) and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) compared to wildtype, and coimmunoprecipitation studies demonstrated enhanced binding of RHOA (165390) to the mutant MAP3K1 complex.


.0005 46,XY SEX REVERSAL 6

MAP3K1, LEU189GLN
  
RCV000495856...

In a 16-year-old 46,XY African American female with complete gonadal dysgenesis (SRXY6; 613762), Granados et al. (2017) identified heterozygosity for a c.566T-A transversion in the MAP3K1 gene, resulting in a leu189-to-gln (L189Q) substitution. Maternal testing was unavailable.


.0006 46,XY SEX REVERSAL 6

MAP3K1, LEU587HIS
  
RCV000495857

In 2 46,XY sisters, one with complete gonadal dysgenesis and the other with partial gonadal dysgenesis (SRXY6; 613762), and their unaffected maternal aunt and affected 46,XY female cousin, Granados et al. (2017) identified heterozygosity for a c.1760T-A transversion in the MAP3K1 gene, resulting in a leu587-to-his (L587H) substitution. The mutation was not found in the ExAC or dbSNP databases. Clinical details were not reported for the affected cousin.


REFERENCES

  1. Antoniou, A. C., Spurdle, A. B., Sinilnikova, O. M., Healey, S., Pooley, K. A., Schmutzler, R. K., Versmold, B., Engel, C., Meindl, A., Arnold, N., Hofmann, W., Sutter, C., and 80 others. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am. J. Hum. Genet. 82: 937-948, 2008. [PubMed: 18355772, images, related citations] [Full Text]

  2. Chamberlin, A., Huether, R., Machado, A. Z., Groden, M., Liu, H.-M., Upadhyay, K., Vivian, O., Gomes, N. L., Lerario, A. M., Nishi, M. Y., Costa, E. M. F., Mendonca, B., Domenice, S., Velasco, J., Loke, J., Ostrer, H. Mutations in MAP3K1 that cause 46,XY disorders of sex development disrupt distinct structural domains in the protein. Hum. Molec. Genet. 28: 1620-1628, 2019. [PubMed: 30608580, related citations] [Full Text]

  3. Easton, D. F., Pooley, K. A., Dunning, A. M., Pharoah, P. D. P., Thompson, D., Ballinger, D. G., Struewing, J. P., Morrison, J., Field, H., Luben, R., Wareham, N., Ahmed, S., and 93 others. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447: 1087-1093, 2007. [PubMed: 17529967, images, related citations] [Full Text]

  4. Espiner, E. A., Veale, A. M., Sands, V. E., Fitzgerald, P. H. Familial syndrome of streak gonads and normal male karyotype in five phenotypic females. New Eng. J. Med. 283: 6-11, 1970. [PubMed: 5419329, related citations] [Full Text]

  5. Granados, A., Alaniz, V. I., Mohnach, L., Barseghyan, H., Vilain, E., Ostrer, H., Quint, E. H., Chen, M., Keegan, C. E. MAP3K1-related gonadal dysgenesis: six new cases and review of the literature. Am. J. Med. Genet. C Semin. Med. Genet. 175C: 253-259, 2017. [PubMed: 28504475, related citations] [Full Text]

  6. Juriloff, D. M., Harris, M. J., Mah, D. G. The open-eyelid mutation, lidgap-Gates, is an eight-exon deletion in the mouse Map3k1 gene. Genomics 85: 139-142, 2005. [PubMed: 15607429, related citations] [Full Text]

  7. Le Caignec, C., Baron, S., McElreavey, K., Joubert, M., Rival, J.-M., Mechinaud, F., David, A. 46,XY gonadal dysgenesis: evidence for autosomal dominant transmission in a large kindred. Am. J. Med. Genet. 116A: 37-43, 2003. [PubMed: 12476449, related citations] [Full Text]

  8. Loke, J., Pearlman, A., Radi, O., Zuffardi, O., Giussani, U., Pallotta, R., Camerino, G., Ostrer, H. Mutations in MAP3K1 tilt the balance from SOX9/FGF9 to WNT/beta-catenin signaling. Hum. Molec. Genet. 23: 1073-1083, 2014. [PubMed: 24135036, related citations] [Full Text]

  9. Lu, Z., Xu, S., Joazeiro, C., Cobb, M. H., Hunter, T. The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. Molec. Cell 9: 945-956, 2002. [PubMed: 12049732, related citations] [Full Text]

  10. Matsuzawa, A., Tseng, P.-H., Vallabhapurapu, S., Luo, J.-L., Zhang, W., Wang, H., Vignali, D. A. A., Gallagher, E., Karin, M. Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex. Science 321: 663-668, 2008. Note: Erratum: Science 322: 375 only, 2008. [PubMed: 18635759, images, related citations] [Full Text]

  11. Minamino, T., Yujiri, T., Papst, P. J., Chan, E. D., Johnson, G. L., Terada, N. MEKK1 suppresses oxidative stress-induced apoptosis of embryonic stem cell-derived cardiac myocytes. Proc. Nat. Acad. Sci. 96: 15127-15132, 1999. [PubMed: 10611349, images, related citations] [Full Text]

  12. Pearlman, A., Loke, J., Le Caignec, C., White, S., Chin, L., Friedman, A., Warr, N., Willan, J., Brauer, D., Farmer, C., Brooks, E., Oddoux, C., and 10 others. Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination. Am. J. Hum. Genet. 87: 898-904, 2010. [PubMed: 21129722, images, related citations] [Full Text]

  13. Roy, S. K., Hu, J., Meng, Q., Xia, Y., Shapiro, P. S., Reddy, S. P. M., Platanias, L. C., Lindner, D. J., Johnson, P. F., Pritchard, C., Pages, G., Pouyssegur, J., Kalvakolanu, D. V. MEKK1 plays a critical role in activating the transcription factor C/EBP-beta-dependent gene expression in response to IFN-gamma. Proc. Nat. Acad. Sci. 99: 7945-7950, 2002. [PubMed: 12048245, images, related citations] [Full Text]

  14. Schlesinger, T. K., Bonvin, C., Jarpe, M. B., Fanger, G. R., Cardinaux, J.-R., Johnson, G. L., Widmann, C. Apoptosis stimulated by the 91-kDa caspase cleavage MEKK1 fragment requires translocation to soluble cellular compartments. J. Biol. Chem. 277: 10283-10291, 2002. [PubMed: 11782455, related citations] [Full Text]

  15. Vinik, B. S., Kay, E. S., Fiedorek, F. T., Jr. Mapping of the MEK kinase gene (Mekk) to mouse chromosome 13 and human chromosome 5. Mammalian Genome 6: 782-783, 1995. [PubMed: 8597633, related citations] [Full Text]

  16. Xia, Y., Wu, Z., Su, B., Murray, B., Karin, M. JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extension. Genes Dev. 12: 3369-3381, 1998. [PubMed: 9808624, images, related citations] [Full Text]

  17. Xu, S., Robbins, D. J., Christerson, L. B., English, J. M., Vanderbilt, C. A., Cobb, M. H. Cloning of rat MEK kinase 1 cDNA reveals an endogenous membrane-associated 195-kDa protein with a large regulatory domain. Proc. Nat. Acad. Sci. 93: 5291-5295, 1996. [PubMed: 8643568, related citations] [Full Text]

  18. Yujiri, T., Sather, S., Fanger, G. R., Johnson, G. L. Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption. Science 282: 1911-1914, 1998. [PubMed: 9836645, related citations] [Full Text]


Bao Lige - updated : 12/10/2019
Marla J. F. O'Neill - updated : 07/17/2017
Paul J. Converse - updated : 07/14/2017
Matthew B. Gross - updated : 4/13/2011
Patricia A. Hartz - updated : 3/30/2011
Marla J. F. O'Neill - updated : 2/16/2011
Paul J. Converse - updated : 8/28/2008
Cassandra L. Kniffin - updated : 4/28/2008
Cassandra L. Kniffin - updated : 7/17/2007
Patricia A. Hartz - updated : 2/2/2005
Stylianos E. Antonarakis - updated : 9/18/2002
Victor A. McKusick - updated : 7/3/2002
Ada Hamosh - updated : 9/20/1999
Creation Date:
Victor A. McKusick : 1/15/1996
mgross : 07/22/2022
mgross : 12/10/2019
alopez : 07/17/2017
mgross : 07/14/2017
carol : 08/29/2011
wwang : 4/25/2011
mgross : 4/13/2011
terry : 3/30/2011
terry : 3/18/2011
wwang : 2/23/2011
terry : 2/16/2011
terry : 11/25/2009
alopez : 11/18/2008
mgross : 8/28/2008
wwang : 5/1/2008
ckniffin : 4/28/2008
carol : 8/17/2007
ckniffin : 7/17/2007
mgross : 2/2/2005
mgross : 9/18/2002
cwells : 7/17/2002
terry : 7/3/2002
carol : 9/21/1999
terry : 9/20/1999
mgross : 9/15/1999
dholmes : 3/24/1998
psherman : 3/17/1998
psherman : 3/16/1998
terry : 3/4/1998
terry : 1/17/1997
mark : 5/13/1996
mark : 1/15/1996

* 600982

MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 1; MAP3K1


Alternative titles; symbols

MAP/ERK KINASE KINASE 1; MEKK1
MAPKKK1
MEK KINASE


HGNC Approved Gene Symbol: MAP3K1

Cytogenetic location: 5q11.2     Genomic coordinates (GRCh38): 5:56,815,549-56,896,152 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
5q11.2 46XY sex reversal 6 613762 Autosomal dominant 3

TEXT

Description

MAP3K1, or MEKK1, is a mitogen-activated protein kinase (MAPK) kinase kinase that regulates the ERK (see 601795) and JNK (see 601158) MAPK pathways, as well as the transcription factor NF-kappa-B (see 164011) and the transcriptional coactivator p300 (EP300; 602700). MAP3K1 generates antiapoptotic signaling as a full-length protein, but it induces apoptosis following cleavage by caspases (see 147678) (summary by Schlesinger et al., 2002).


Cloning and Expression

Xia et al. (1998) cloned human MEKK1 from HeLa, B-cell, and Jurkat cDNA libraries. The deduced 1,495-amino acid protein has a C-terminal catalytic domain and shares 83% identity with rat Mekk1. Western blot analysis detected MEKK1 at an apparent molecular mass of 200 kD in transfected COS-1 cells.

Xu et al. (1996) cloned rat Mekk1. The deduced 1,493-amino acid rat Mekk1 protein contains 2 N-terminal proline-rich domains, followed by a cysteine-rich region, 2 pleckstrin (PLEK; 173570) homology (PH) domains, and a C-terminal kinase domain. Western blot analysis detected endogenous MEKK1 at an apparent molecular mass of about 195 kD in human 293 cells. Mekk1 proteins with similar molecular masses were detected in mouse, rat, and Chinese hamster cell lines. Fractionation of cells expressing rat Mekk1 revealed that the full-length protein associated with membranes. A Mekk1 C-terminal catalytic domain fragment associated with both the soluble fraction and with membranes.

Pearlman et al. (2010) demonstrated high levels of expression of Map3k1 in mouse gonads within 13.5 days postcoitum (dpc), with approximately equal expression in male and female gonads. Map3k1 expression was also observed throughout the mouse embryonic gonad at 11.5 dpc, the sex-determining stage of gonad development. Staining occurred within the testis cords at 13.5 dpc in a pattern indicative of Sertoli cell expression.


Gene Structure

Pearlman et al. (2010) noted that the MAP3K1 gene contains 20 exons.


Mapping

Vinik et al. (1995) identified DNA sequence and size polymorphisms in intronic and 3-prime untranslated regions of the mouse Map3k1 gene and the human MAP3K1 homolog. Using these allele-specific polymorphisms, they mapped the Map3k1 gene in an intersubspecific backcross to mouse chromosome 13. They mapped the human MAP3K1 gene to chromosome 5 by somatic cell hybrid analysis.


Gene Function

By assaying transfected COS-1 cells, Xia et al. (1998) showed that human MEKK1 activated JNK1 (MAPK8; 601158) robustly and p38-alpha (MAPK14; 600289) less efficiently, but it had only a marginal effect on ERK2 (MAPK1; 176948). MEKK1 directly and specifically interacted with JNKK1 (MAP2K4; 601335) and activated JNKK1 in cells and in vitro. Phosphorylation of JNKK1 by MEKK1 disrupted their interaction. MEKK1 and JNK1 competed for binding to JNKK1. Xia et al. (1998) concluded that JNKK1 is the preferred MEKK1 substrate.

Gamma-interferon (IFNG; 147570) induces a number of genes, including MEKK1, to upregulate cellular responses by using specific transcription factors and the cognate elements (Roy et al., 2002).

Lu et al. (2002) found that the PHD domain of MEKK1, a RING finger-like structure, exhibited E3 ubiquitin ligase activity toward ERK2 in vitro and in vivo. Moreover, both MEKK1 kinase activity and the docking motif on ERK1 (601795)/ERK2 were involved in ERK1/ERK2 ubiquitination. Significantly, cells expressing ERK2 with the docking motif mutation were resistant to sorbitol-induced apoptosis. Therefore, MEKK1 functions not only as an upstream activator of ERK and JNK through its kinase domain, but also as an E3 ligase through its PHD domain, providing a negative regulatory mechanism for decreasing ERK1/ERK2 activity.

Schlesinger et al. (2002) stated that full-length mouse Mekk1 generates antiapoptotic signals, while a 91-kD C-terminal Mekk1 fragment induces apoptosis. They found that caspase-dependent cleavage of Mekk1 relocalized the 91-kD fragment from the particulate fraction to a soluble cytoplasmic fraction. Schlesinger et al. (2002) concluded that MEKK1 functions as a molecular switch to regulate apoptosis in a caspase-dependent manner.

Cytokine signaling is thought to require assembly of multicomponent signaling complexes at cytoplasmic segments of membrane-embedded receptors, in which receptor-proximal protein kinases are activated. Matsuzawa et al. (2008) reported that, upon ligation, CD40 (109535) formed a complex containing adaptor molecules TRAF2 (601895) and TRAF3 (601896), ubiquitin-conjugating enzyme UBC13 (UBE2N; 603679), cellular inhibitor of apoptosis protein-1 (CIAP1, or BIRC2; 601712) and -2 (CIAP2, or BIRC3; 601721), IKK-gamma (IKBKG; 300248), and MEKK1. TRAF2, UBC13, and IKK-gamma were required for complex assembly and activation of MEKK1 and MAP kinase cascades. However, the kinases were not activated unless the complex was translocated from the membrane to the cytosol upon CIAP1/CIAP2-induced degradation of TRAF3. Matsuzawa et al. (2008) proposed that this 2-stage signaling mechanism may apply to other innate immune receptors and may account for spatial and temporal separation of MAPK and IKK signaling.


Molecular Genetics

Association with Breast Cancer

Easton et al. (2007) identified an A/C SNP (rs889312) in the MAP3K1 gene that was significantly (p = 7 x 10(-20)) associated with familial breast cancer (114480) in a 3-stage genomewide association study of 22,848 cases from 22 studies. Easton et al. (2007) found that the allele was common in the U.K. population and thus unlikely to confer increased disease risk individually. However, in combination with other susceptibility alleles, the SNP may become clinically significant.

In a sample of 10,358 carriers of BRCA1 (113705) or BRCA2 (600185) gene mutations from 23 studies, Antoniou et al. (2008) did not observe an overall association between rs889312 and increased risk of breast cancer. However, when the group was stratified, BRCA2 mutation carriers who also carried the minor allele of the SNP were at slightly increased risk (hazard ratio of 1.12; p(trend) = 0.02). The authors concluded that this locus interacts multiplicatively on breast cancer risk in BRCA2 mutation carriers.

46,XY Sex Reversal 6

In a French family with 46,XY gonadal dysgenesis mapping to chromosome 5q (SRXY6; 613762), Pearlman et al. (2010) analyzed the MAP3K1 gene and identified a heterozygous splice site mutation that segregated with disease in the family (600982.0001). Sequence analysis of MAP3K1 in a New Zealand family with 46,XY gonadal dysgenesis identified a missense mutation (600982.0002). Screening of MAP3K1 in 11 sporadic cases revealed 2 more missense mutations in 2 patients (600982.0003 and 600982.0004, respectively). In cultured primary lymphoblastoid cells from the French family and 2 sporadic patients, the mutations were found to alter phosphorylation of the downstream targets p38 (MAPK14; 600289) and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) and to enhance binding of RHOA (165390) to the MAP3K1 complex.

Using human B-cell lymphoblastoid cell lines and NT2/D1 human teratocarcinoma cells, Loke et al. (2014) found that MAP3K1 splicing and missense mutations associated with gonadal dysgenesis increased phosphorylation of p38 and ERK1/ERK2 and binding of RHOA, MAP3K4 (602425), FRAT1 (602503), and AXIN1 (603816). Overexpression of RHOA or reducing expression of MAP3K4 phenocopied the MAP3K1 mutations in NT2/D1 cells. The effects of the MAP3K1 mutations were rescued by cotransfection with wildtype MAP3K4. Loke et al. (2014) concluded that, although MAP3K1 is not usually required for testis determination, MAP3K1 mutations can disrupt normal development through gains of function.

In 7 46,XY females with complete or partial gonadal dysgenesis from 4 unrelated families, Granados et al. (2017) identified heterozygosity for mutations in the MAP3K1 gene (see, e.g., 600982.0005 and 600982.0006).

Using structural modeling and functional data, Chamberlin et al. (2019) examined MAP3K1 mutations associated with 46,XY gonadal dysgenesis. These pathogenic mutations clustered in the guanine exchange factor (GEF), plant homeodomain (PHD), and armadillo repeat (ARM) domains and disrupted their structures, resulting in overactivation of MAP3K1 kinase signaling and disruption of the testis development pathway.


Animal Model

Yujiri et al. (1998) targeted disruption of the gene encoding Mekk1 to define its function in the regulation of MAP kinase pathways and cell survival. Mekk1 -/- embryonic stem cells from mice had lost or altered responses of Jnk to microtubule disruption and cold stress but activated Jnk normally in response to heat shock, anisomycin, and ultraviolet irradiation. Activation of Jnk was lost and that of Erk was diminished in response to hyperosmolarity and serum factors in Mekk1 -/- cells. Loss of Mekk1 expression resulted in a greater apoptotic response of cells to hyperosmolarity and microtubule disruption. When activated by specific stresses that alter cell shape and the cytoskeleton, Mekk1 signals to protect cells from apoptosis.

Minamino et al. (1999) found that Mekk1 -/- mouse embryonic stem cell-derived cardiac myocytes were extremely sensitive to hydrogen peroxide-induced apoptosis. Elevated sensitivity was due to enhanced Tnf-alpha (TNF; 191160) production, which was negatively regulated by the Mekk1-Jnk pathway in wildtype mice.

The BALB/cGa mouse strain and its descendants produced 2 waves of high frequency of spontaneous heritable mutations. Juriloff et al. (2005) determined that one of these mutations, referred to as ophthalmatrophy (oa) or lidgap-Gates (lg-Ga), is a 27.5-kb deletion of exons 2 to 9 of the Map3k1 gene. The mutation causes a failure of fetal eyelid development, resulting in the defect 'open eyelids at birth.' Affected eyes develop corneal opacity by adulthood.


ALLELIC VARIANTS 6 Selected Examples):

.0001   46,XY SEX REVERSAL 6

MAP3K1, IVS2AS, T-A, -8
SNP: rs1131692053, ClinVar: RCV000023055

In 5 affected individuals from a large multigenerational French family with 46,XY gonadal dysgenesis, complete or partial (SRXY6; 613762), originally reported by Le Caignec et al. (2003), Pearlman et al. (2010) identified heterozygosity for a splice acceptor site mutation (634-8T-A) in intron 2 of MAP3K1, resulting in the insertion of 2 amino acids in-frame at this site. Two mutation-positive individuals were phenotypic females who on laparotomy had right-sided streak gonads and left-sided dysgenetic testes, with a dysgerminoma of the right streak gonad in one patient and a dysgerminoma and gonadoblastoma of the left dysgenetic testis in the other patient. The other 3 mutation-positive family members were phenotypic males, 1 with penile hypospadias and chordee, and the 2 other with perineal hypospadias, 1 of whom also had chordee. The ratio of mutant to wildtype transcript was greater than 1 in lymphoblastoid cells from affected individuals. The mutation was not found in 100 unrelated French controls of European descent or in the 1000 Genomes Project. In cultured primary lymphoblastoid cells, the mutation was found to increase phosphorylation of the downstream targets p38 (MAPK14; 600289) and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) compared to wildtype; coimmunoprecipitation studies demonstrated enhanced binding of RHOA (165390) to the mutant MAP3K1 complex.


.0002   46,XY SEX REVERSAL 6

MAP3K1, GLY616ARG
SNP: rs143853590, gnomAD: rs143853590, ClinVar: RCV000023056, RCV002247381

In affected individuals from a 3-generation New Zealand family of European descent with 46,XY gonadal dysgenesis, complete or partial (SRXY6; 613762), originally reported by Espiner et al. (1970), Pearlman et al. (2010) identified heterozygosity for a 1846G-A transition in exon 10 of the MAP3K1 gene, resulting in a gly616-to-arg (G616R) substitution. The mutation was not found in 100 unrelated ethnically matched controls or in the 1000 Genomes Project. A patient cell line from this family was not available for analysis.


.0003   46,XY SEX REVERSAL 6

MAP3K1, LEU189PRO
SNP: rs387906788, ClinVar: RCV000023057, RCV003407356

In a sporadic patient with 46,XY complete gonadal dysgenesis (SRXY6; 613762), Pearlman et al. (2010) identified heterozygosity for a 566T-C transition in exon 2 of the MAP3K1 gene, resulting in a leu189-to-pro (L189P) substitution within the phylogenetically conserved focal adhesion kinase (FAK) binding site. The mutation was not found in 100 unrelated ethnically matched controls or in the 1000 Genomes Project. In cultured primary lymphoblastoid cells, the mutation was found to increase phosphorylation of the downstream target ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) compared to wildtype, and coimmunoprecipitation studies demonstrated enhanced binding of RHOA (165390) to the mutant MAP3K1 complex.


.0004   46,XY SEX REVERSAL 6

MAP3K1, LEU189ARG
SNP: rs387906788, ClinVar: RCV000023058

In a sporadic patient with 46,XY complete gonadal dysgenesis (613762), Pearlman et al. (2010) identified heterozygosity for a 566T-G transversion in exon 2 of the MAP3K1 gene, resulting in a leu189-to-arg (L189R) substitution within the phylogenetically conserved focal adhesion kinase (FAK) binding site. The mutation was not found in 100 unrelated ethnically matched controls or in the 1000 Genomes Project. In cultured primary lymphoblastoid cells, the mutation was found to increase phosphorylation of the downstream targets p38 (MAPK14; 600289) and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) compared to wildtype, and coimmunoprecipitation studies demonstrated enhanced binding of RHOA (165390) to the mutant MAP3K1 complex.


.0005   46,XY SEX REVERSAL 6

MAP3K1, LEU189GLN
SNP: rs387906788, ClinVar: RCV000495856, RCV000624691

In a 16-year-old 46,XY African American female with complete gonadal dysgenesis (SRXY6; 613762), Granados et al. (2017) identified heterozygosity for a c.566T-A transversion in the MAP3K1 gene, resulting in a leu189-to-gln (L189Q) substitution. Maternal testing was unavailable.


.0006   46,XY SEX REVERSAL 6

MAP3K1, LEU587HIS
SNP: rs1131692186, ClinVar: RCV000495857

In 2 46,XY sisters, one with complete gonadal dysgenesis and the other with partial gonadal dysgenesis (SRXY6; 613762), and their unaffected maternal aunt and affected 46,XY female cousin, Granados et al. (2017) identified heterozygosity for a c.1760T-A transversion in the MAP3K1 gene, resulting in a leu587-to-his (L587H) substitution. The mutation was not found in the ExAC or dbSNP databases. Clinical details were not reported for the affected cousin.


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Contributors:
Bao Lige - updated : 12/10/2019
Marla J. F. O'Neill - updated : 07/17/2017
Paul J. Converse - updated : 07/14/2017
Matthew B. Gross - updated : 4/13/2011
Patricia A. Hartz - updated : 3/30/2011
Marla J. F. O'Neill - updated : 2/16/2011
Paul J. Converse - updated : 8/28/2008
Cassandra L. Kniffin - updated : 4/28/2008
Cassandra L. Kniffin - updated : 7/17/2007
Patricia A. Hartz - updated : 2/2/2005
Stylianos E. Antonarakis - updated : 9/18/2002
Victor A. McKusick - updated : 7/3/2002
Ada Hamosh - updated : 9/20/1999

Creation Date:
Victor A. McKusick : 1/15/1996

Edit History:
mgross : 07/22/2022
mgross : 12/10/2019
alopez : 07/17/2017
mgross : 07/14/2017
carol : 08/29/2011
wwang : 4/25/2011
mgross : 4/13/2011
terry : 3/30/2011
terry : 3/18/2011
wwang : 2/23/2011
terry : 2/16/2011
terry : 11/25/2009
alopez : 11/18/2008
mgross : 8/28/2008
wwang : 5/1/2008
ckniffin : 4/28/2008
carol : 8/17/2007
ckniffin : 7/17/2007
mgross : 2/2/2005
mgross : 9/18/2002
cwells : 7/17/2002
terry : 7/3/2002
carol : 9/21/1999
terry : 9/20/1999
mgross : 9/15/1999
dholmes : 3/24/1998
psherman : 3/17/1998
psherman : 3/16/1998
terry : 3/4/1998
terry : 1/17/1997
mark : 5/13/1996
mark : 1/15/1996