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this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

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Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Human MAP3K1/MEKK1 (UniProt Q13233): Functional Annotation Research Report

Executive summary

The target identity is verified. MAP3K1 is the approved human gene encoding mitogen-activated protein kinase kinase kinase 1, commonly called MEKK1; the literature describes the same approximately 196-kDa, 1,512-residue protein and the same C-terminal kinase plus N-terminal regulatory architecture as UniProt Q13233. No evidence was conflated with MAP3K2/MEKK2, MAP3K3/MEKK3, or nonhuman MEKK1 orthologues except where animal models are explicitly identified. (pham2013map3k1genomicalterations pages 1-3, bohlesUnknownyearautoregulationdynamicsof pages 24-28)

MAP3K1 is best regarded as a multifunctional intracellular stress- and cytoskeleton-responsive signaling enzyme with two catalytic activities. Its primary kinase function is ATP-dependent phosphorylation of MAP kinase kinases, with MAP2K4/MKK4 the best-supported preferred substrate, thereby driving the MKK4/MKK7–JNK–c-Jun cascade. Context-dependent coupling to MKK1/2–ERK also occurs. A RING/PHD-like domain additionally supplies E3 ubiquitin-ligase activity, enabling degradation-linked ubiquitylation of ERK1/2 and c-Jun and nondegradative Lys63-linked ubiquitylation of TAB1. Thus, MAP3K1 integrates phosphorylation, ubiquitin signaling, cytoskeletal state, and cell-fate decisions rather than acting as a simple linear MAP3K. (lu2002thephddomain pages 2-3, witowsky2003ubiquitylationofmekk1 pages 1-2, xia2007mekk1mediatesthe pages 1-2, charlaftis2014themekk1phd pages 1-2)

Table: Concise evidence-based annotation of human MAP3K1/MEKK1 (Q13233), covering its identity, domains, dual catalytic activities, localization, pathways, and major disease associations. Confidence notes distinguish established mechanisms from context-dependent or incompletely replicated findings.

1. Identity verification and protein architecture

1.1 Correct gene and organism

The supplied record is internally and externally consistent:

• Gene: MAP3K1
• Accepted synonyms: MAPKKK1, MEKK, MEKK1
• Protein: mitogen-activated protein kinase kinase kinase 1/MEK kinase 1
• Organism: Homo sapiens
• UniProt: Q13233
• Length and mass: 1,512 amino acids and approximately 196 kDa

The retrieved human literature explicitly equates MAP3K1 with MEKK1 and reports the matching length, molecular mass, kinase identity, and unusual ubiquitin-ligase architecture. The target is therefore unambiguous for this report. (pham2013map3k1genomicalterations pages 1-3, bohlesUnknownyearautoregulationdynamicsof pages 24-28)

1.2 Domain organization

MAP3K1 has a large N-terminal regulatory region and a C-terminal protein-kinase domain, reported at residues 1243–1508. Its N-terminal region includes a SWIM zinc-binding domain, a structurally resolved TOG domain, and a RING-like domain historically called a PHD domain; tandem ubiquitin-interacting motifs precede the kinase region. A caspase-3 cleavage site at Asp878 separates much of the regulatory region from the C-terminal catalytic fragment. (pham2013map3k1genomicalterations pages 1-3, bohlesUnknownyearautoregulationdynamicsof pages 24-28, filipcik2020acryptictubulinbindinga pages 1-2)

This architecture aligns with the supplied InterPro assignments: ARM/HEAT-like helical folds are compatible with the six-HEAT-repeat TOG structure, while the C terminus belongs to the STE-family protein-kinase/MAP3K group. MAP3K1 is unusual among MAP3Ks because it combines a kinase with an intrinsic RING/PHD-like E3 ubiquitin ligase. (bohlesUnknownyearautoregulationdynamicsof pages 28-31, charlaftis2014themekk1phd pages 1-2)

2. Primary biochemical function

2.1 Protein-kinase reaction

MAP3K1 catalyzes the conventional protein-kinase reaction:

ATP + MAP2K protein → ADP + phosphorylated MAP2K protein.

The enzyme phosphorylates activation-loop serine/threonine residues in downstream MAP2Ks. Oligomerization supports trans-autophosphorylation and activation, although detailed catalytic constants and a universal short peptide-recognition consensus are not established by the retrieved evidence. (bohlesUnknownyearautoregulationdynamicsofa pages 169-173, lu2002thephddomain pages 2-3)

2.2 Direct substrates and specificity

MKK4/MAP2K4 is the most strongly supported preferred kinase substrate. Biochemical work reports the greatest MEKK1 activity toward MKK4, which then activates JNK. MAP3K1 can also directly phosphorylate MKK1/MAP2K1, supporting ERK1/2 activation, and signaling through MKK7/MAP2K7 contributes to JNK activation. The physiologically dominant route is therefore best annotated as MAP3K1 → MKK4/MKK7 → JNK, with MKK1/2–ERK signaling treated as stimulus- and cellular-context-dependent rather than equally preferred. (lu2002thephddomain pages 2-3, witowsky2003ubiquitylationofmekk1 pages 1-2, charlaftis2014themekk1phd pages 1-2)

MAP3K1 does not phosphorylate c-Jun directly in the canonical cascade: MKK4 and MKK7 activate JNK, and JNK phosphorylates c-Jun. This distinction is important because MAP3K1 separately regulates c-Jun abundance through its E3-ligase activity. (bohlesUnknownyearautoregulationdynamicsof pages 24-28, xia2007mekk1mediatesthe pages 1-2)

2.3 E3 ubiquitin-ligase reaction

The RING/PHD-like domain recruits a ubiquitin-charged E2 and promotes transfer of ubiquitin to substrate lysines. Unlike a HECT ligase, it functions primarily as an E2–substrate adaptor rather than forming a catalytic ubiquitin thioester. PHD/RING mutations markedly impair ubiquitylation, while intact kinase activity and full-length organization can also be required for efficient cellular autoubiquitylation. (lu2002thephddomain pages 3-5, xia2007mekk1mediatesthe pages 1-2, witowsky2003ubiquitylationofmekk1 pages 2-3)

Three mechanistically important substrates illustrate the range of outcomes:

1. ERK1/2: Under hyperosmotic stress, MAP3K1 associates with ERK1/2, polyubiquitylates it, and promotes proteasome-dependent degradation. MG132 prevented ERK loss, whereas MEK inhibition blocked ERK activation but not degradation, separating the proteolytic effect from conventional MEK–ERK activation. Purified-domain and cellular experiments supported direct ERK2 ubiquitylation and showed impairment by kinase- or PHD-defective MAP3K1. [Lu et al., Molecular Cell, May 2002; DOI: https://doi.org/10.1016/S1097-2765(02)00519-1]. (lu2002thephddomain pages 2-3, lu2002thephddomain pages 3-5)

2. c-Jun: During osmotic stress, MAP3K1 promotes c-Jun ubiquitylation and proteasomal degradation. In rat fibroblasts, c-Jun loss was evident by approximately 6 hours after sorbitol treatment; MAP3K1 deficiency blocked the response, and c-Jun overexpression reduced osmotic-stress-induced apoptosis. [Xia et al., Molecular and Cellular Biology, January 2007; DOI: https://doi.org/10.1128/MCB.01355-06]. (xia2007mekk1mediatesthe pages 1-2)

3. TAB1: MAP3K1 uses UBE2N–UBE2V1 to transfer predominantly Lys63-linked, nondegradative ubiquitin chains to TAB1. This promotes TAB1–TAK1 signaling and cytokine-induced JNK/p38 activation. An E3-defective Map3k1 knock-in impaired responses to TGF-β, EGF, and nocodazole without destabilizing the MAPKs, supporting a signaling rather than degradative mechanism. Much of this physiological evidence derives from mouse embryonic stem cells and should be extrapolated to human MAP3K1 cautiously. [Charlaftis et al., EMBO Journal, September 26, 2014; DOI: https://doi.org/10.15252/embj.201488351]. (charlaftis2014themekk1phd pages 1-2, charlaftis2014themekk1phd pages 2-3)

MAP3K1 ubiquitylation can also inhibit its own ability to phosphorylate MKK1 and MKK4. In HEK293 experiments, kinase-inactive MAP3K1 generated less than 10% of the wild-type ubiquitylation signal, and mutation of PHD residue Cys441 markedly reduced ubiquitylation. This provides an autoregulatory brake connecting the kinase and ubiquitin systems. [Witowsky and Johnson, Journal of Biological Chemistry, January 2003; DOI: https://doi.org/10.1074/jbc.C200616200]. (witowsky2003ubiquitylationofmekk1 pages 1-2, witowsky2003ubiquitylationofmekk1 pages 2-3)

3. Signaling pathways and regulation

3.1 Core pathway

The best-supported core pathway is:

cytoskeletal, osmotic, cytokine, receptor, or genotoxic stress → MAP3K1 → MKK4/MKK7 → JNK → c-Jun and other JNK substrates.

MAP3K1 additionally influences MKK1/2–ERK1/2, p38, TAK1, NF-κB, and p53-related signaling. These broader outputs should not be interpreted as constitutive: pathway selection depends on stimulus, binding partners, subcellular recruitment, ubiquitin-chain topology, and whether MAP3K1 remains full-length or is proteolytically cleaved. (pham2013map3k1genomicalterations pages 1-3, bohlesUnknownyearautoregulationdynamicsof pages 24-28, charlaftis2014themekk1phd pages 1-2)

3.2 Cytoskeleton sensing

MAP3K1 is particularly responsive to perturbations of cell shape and cytoskeletal dynamics. The cryptic TOG domain preferentially binds curved α/β-tubulin heterodimers, which occur in soluble tubulin and at polymerizing or depolymerizing microtubule ends. Its crystal structure contains six HEAT-repeat helix–loop–helix units. Mutations disrupting this interaction reduce microtubule density at the leading edge of polarized cells, providing a direct molecular bridge from microtubule state to MAP3K1 signaling and migration. [Filipčík et al., PNAS, August 2020; DOI: https://doi.org/10.1073/pnas.2006429117]. (bohlesUnknownyearautoregulationdynamicsof pages 28-31, filipcik2020acryptictubulinbindinga pages 1-2)

This mechanism is relevant to microtubule-targeting chemotherapy: such agents activate MAP3K1-dependent stress responses, while tumor-derived mutations recur at the TOG–tubulin interface. That observation is biologically suggestive but does not yet establish a clinically validated predictive biomarker. (bohlesUnknownyearautoregulationdynamicsof pages 28-31, filipcik2020acryptictubulinbindinga pages 1-2)

3.3 Proteolytic cell-fate switch

Full-length MAP3K1 often supports survival, migration, and organized stress adaptation. Caspase-3 cleavage at Asp878 releases a C-terminal kinase-containing fragment associated with sustained JNK signaling and apoptosis. Consequently, apparently contradictory survival and death phenotypes can reflect different stimuli, localization, signal duration, and proteolytic state rather than inconsistent enzyme function. (pham2013map3k1genomicalterations pages 1-3, filipcik2020acryptictubulinbindinga pages 1-2)

4. Subcellular localization

MAP3K1 is an intracellular, dynamically recruited signaling protein rather than a constitutive resident of one organelle. Reported locations include:

• Perinuclear cytoplasm, where endogenous MAP3K1 and ERK2 colocalized during osmotic-stress studies.
• Plasma-membrane-associated complexes.
• Actin stress fibers and focal adhesions, through interactions involving α-actinin and focal-adhesion machinery.
• Epithelial tight junctions, where MARVELD3-dependent recruitment can restrain MEKK1–JNK signaling.
• Leading edges and dynamic microtubule sites in polarized/migrating cells through TOG-domain binding to curved tubulin.

These locations position MAP3K1 to detect changes in adhesion, junction integrity, mechanical/cytoskeletal organization, and microtubule dynamics. Localization is partner- and stimulus-dependent; assigning it simply as “cytosolic” would omit a central feature of its regulation. (filipcik2020acryptictubulinbindinga pages 1-2, lu2002thephddomain pages 2-3, lu2002thephddomain pages 3-5)

5. Biological functions supported by mechanistic evidence

The most defensible functional annotation is integration of stress and cytoskeletal inputs into MAPK and ubiquitin-dependent outputs controlling cell migration, epithelial morphogenesis, survival, and apoptosis. Developmental mouse genetics additionally supports roles in eyelid closure, ocular morphogenesis, immune-cell development, and auditory-system organization, but these pleiotropic phenotypes are downstream consequences of the core signaling mechanism rather than separate biochemical functions. (bohlesUnknownyearautoregulationdynamicsof pages 24-28, charlaftis2014themekk1phd pages 1-2)

Human genetics particularly supports a role in sex determination. Disease-associated heterozygous MAP3K1 variants often enhance RhoA-associated signaling and increase ERK phosphorylation, with a smaller increase in p38, shifting the balance between testis- and ovary-promoting developmental programs. These variants are generally interpreted as context-specific gain-of-function alleles, unlike the loss-of-function alterations frequent in luminal breast tumors. (lu2025anovelvariant pages 1-2, pham2013map3k1genomicalterations pages 4-5)

6. Recent research, 2023–2024

6.1 Recessive nonsyndromic deafness, DFNB128—2024

Faridi and colleagues reported homozygous MAP3K1 c.4460G>A, p.Arg1487His, affecting a highly conserved residue in the kinase domain, in two affected siblings from a consanguineous Pakistani family. The two siblings had severe-to-profound or profound bilateral sensorineural hearing loss; both parents and unaffected siblings were heterozygous carriers. The study used approximately 960,919 SNP markers, homozygosity mapping, exome sequencing, and Sanger confirmation. (faridi2024deafnessdfnb128associated pages 2-4, faridi2024deafnessdfnb128associated pages 6-8)

The allele was observed in only 3 of 1,613,810 population chromosomes and was absent from 348 ethnically matched control chromosomes. No convincing biallelic alternative was found among the other genes in the shared 1.2-Mb interval. Supporting evidence included conserved sequence/structural modeling, cochlear single-cell expression, and two recessive deaf Map3k1 mouse models. [Faridi et al., Genes 15:845, published June 2024; DOI: https://doi.org/10.3390/genes15070845]. (faridi2024deafnessdfnb128associated pages 11-13, faridi2024deafnessdfnb128associated pages 10-11, faridi2024deafnessdfnb128associated pages 6-8)

The evidence remains provisional: only one human family was identified, Arg1487His was not functionally tested in a direct kinase assay, and linkage disequilibrium with an undiscovered variant cannot be completely excluded. The correct annotation is therefore “strong candidate association with autosomal-recessive nonsyndromic deafness,” not yet an extensively replicated genotype–phenotype relationship. (faridi2024deafnessdfnb128associated pages 11-13, faridi2024deafnessdfnb128associated pages 10-11)

6.2 JNK pathway as a breast-cancer suppressor—2023

Itah et al. examined the pathway consequence expected from loss-of-function alterations in MAP3K1, MAP2K4, and MAP2K7. In human mammary epithelial cells, CRISPR disruption of MAPK8/MAPK9 or MAP2K4/MAP2K7 did not change two-dimensional growth but promoted continued proliferation and enlarged multi-acinar structures in three-dimensional culture. HER2 activation and JNK loss caused similar transcriptional changes. (itah2023her2drivenbreastcancer pages 1-2, itah2023her2drivenbreastcancer pages 8-10)

In mouse mammary epithelium, JNK or upstream MAP2K deficiency accelerated HER2-driven breast-tumor development. Genomic analyses compared six wild-type and seven JNK-deficient tumor lines; deficient tumors showed increased structural variation, including significantly more high-impact exon-associated inversions. [Itah et al., PNAS, published January 19, 2023; DOI: https://doi.org/10.1073/pnas.2218373120]. (itah2023her2drivenbreastcancer pages 1-2, itah2023her2drivenbreastcancer pages 8-10)

This is compelling pathway-level evidence that the MAP3K1–MKK4/7–JNK axis can suppress HER2-driven tumorigenesis. It is not, however, a MAP3K1-specific knockout study; therefore, it supports the functional interpretation of MAP3K1 loss but does not prove that every MAP3K1 alteration has the same phenotype. (itah2023her2drivenbreastcancer pages 10-11, itah2023her2drivenbreastcancer pages 8-10)

7. Disease relevance and quantitative data

7.1 Cancer

MAP3K1’s cancer role is strongly context-dependent. In luminal breast cancer, alterations are predominantly predicted loss-of-function: one reported spectrum comprised 59% frameshift insertions/deletions and 19% nonsense mutations, without a recurrent hotspot. Approximately 50% of tumors with MAP3K1 or MAP2K4 alterations also carried activating PIK3CA mutations, suggesting cooperating PI3K activation and JNK-pathway attenuation. Conversely, amplification or increased expression was reported in approximately 5% of melanomas, where activated C-terminal signaling may support ERK and proliferation. (pham2013map3k1genomicalterations pages 5-7)

Open Targets independently aggregates MAP3K1 associations with breast adenocarcinoma/carcinoma, ovarian cancer, 46,XY sex reversal, and partial gonadal dysgenesis. Such association scores are evidence-integration outputs rather than clinical actionability ratings. (OpenTargets Search: -MAP3K1)

The expert interpretation is therefore not “MAP3K1 is always oncogenic” or “always a tumor suppressor.” Full-length versus truncated protein, tissue lineage, mutation class, and pathway wiring determine the outcome. Inactivating mutations can suppress JNK-mediated tumor restraint in breast cancer, whereas amplification, cleavage, or sustained kinase output can be growth- or death-promoting elsewhere. (pham2013map3k1genomicalterations pages 1-3, itah2023her2drivenbreastcancer pages 1-2, pham2013map3k1genomicalterations pages 5-7)

7.2 46,XY differences/disorders of sex development

Pathogenic heterozygous MAP3K1 variants are established causes of 46,XY gonadal dysgenesis/sex reversal. An influential cohort estimated MAP3K1 variants in about 18% of sporadic 46,XY gonadal-dysgenesis cases, although this frequency should not be generalized across ancestries or differently ascertained DSD cohorts. Patient-derived cells showed increased ERK and, to a lesser degree, p38 phosphorylation; implicated variants cluster in regulatory interaction regions and can enhance RhoA binding. (lu2025anovelvariant pages 1-2, pham2013map3k1genomicalterations pages 4-5)

7.3 Hearing loss

The 2024 DFNB128 report expands the allelic model: dominant regulatory gain-of-function variants are associated with sex-development phenotypes, whereas a subtle homozygous kinase-domain variant may cause isolated deafness. Mouse cochlear data support MAP3K1 expression in spiral-ganglion and epithelial/supporting-cell populations, but the precise human cellular lesion remains unresolved. (faridi2024deafnessdfnb128associated pages 10-11, faridi2024deafnessdfnb128associated pages 2-4, faridi2023deafnessdfnb110associated pages 7-10)

8. Applications and translational status

Molecular diagnostics

MAP3K1 is already relevant to diagnostic sequencing and variant interpretation in 46,XY DSD, breast-tumor genomic profiling, and potentially recessive hearing-loss panels. Interpretation must be allele-specific: truncating somatic cancer variants, regulatory DSD gain-of-function variants, and homozygous kinase-domain variants should not be assigned a common mechanism. The 2024 deafness association requires independent replication before it can support high-confidence clinical action on its own. (faridi2024deafnessdfnb128associated pages 10-11, pham2013map3k1genomicalterations pages 4-5, pham2013map3k1genomicalterations pages 5-7)

Cancer stratification

MAP3K1 or MAP2K4 loss can identify tumors with attenuated JNK signaling, particularly in luminal breast cancer, and may help define biological subgroups alongside PIK3CA status. At present, the evidence supports mechanistic stratification and research use more strongly than a standard MAP3K1-directed treatment decision. (itah2023her2drivenbreastcancer pages 1-2, pham2013map3k1genomicalterations pages 5-7)

Drug development

Potential intervention points include the C-terminal kinase, the TOG–tubulin interface, the RING/E2 interaction, and downstream JNK or ERK nodes. Direct systemic inhibition is intrinsically risky because MAP3K1 can be tumor-suppressive, pro-survival, or pro-apoptotic depending on tissue and stimulus. A successful strategy would likely require genotype-, lineage-, and pathway-state selection rather than indiscriminate MAP3K1 blockade. The retrieved 2023–2024 literature does not establish an approved MAP3K1-selective therapy or a validated clinical companion biomarker.

9. Evidence-weighted annotation

Recommended primary annotation:

Human MAP3K1/MEKK1 is a dynamically localized STE-family MAP kinase kinase kinase and RING-type E3 ubiquitin ligase. It preferentially phosphorylates MKK4 and activates MKK4/MKK7–JNK signaling in response to cytoskeletal and cellular stress, while contextually coupling to MKK1/2–ERK and p38/TAK1 pathways. Its SWIM/TOG/RING-containing regulatory region recruits cytoskeletal and ubiquitin-system components; its TOG domain binds curved tubulin, and its RING/PHD-like domain ubiquitylates ERK1/2, c-Jun, TAB1, and MAP3K1 itself. Spatial recruitment and caspase cleavage determine whether signaling favors migration/survival or apoptosis.

Confidence: high for identity, kinase/E3 dual activity, MKK4 preference, JNK coupling, TOG–tubulin binding, and stress-dependent ERK/c-Jun/TAB1 ubiquitylation; moderate for the relative importance of ancillary pathways in any one human tissue; provisional for MAP3K1 p.Arg1487His as a replicated human deafness allele.

Key source list

• Pham TT, Angus SP, Johnson GL. “MAP3K1: Genomic Alterations in Cancer and Function in Promoting Cell Survival or Apoptosis.” Genes & Cancer. November 2013. https://doi.org/10.1177/1947601913513950. (pham2013map3k1genomicalterations pages 1-3, pham2013map3k1genomicalterations pages 5-7)
• Lu Z et al. “The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2.” Molecular Cell. May 2002. https://doi.org/10.1016/S1097-2765(02)00519-1. (lu2002thephddomain pages 2-3, lu2002thephddomain pages 3-5)
• Xia Y et al. “MEKK1 Mediates the Ubiquitination and Degradation of c-Jun in Response to Osmotic Stress.” Molecular and Cellular Biology. January 2007. https://doi.org/10.1128/MCB.01355-06. (xia2007mekk1mediatesthe pages 1-2)
• Charlaftis N et al. “The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines.” EMBO Journal. September 26, 2014. https://doi.org/10.15252/embj.201488351. (charlaftis2014themekk1phd pages 1-2, charlaftis2014themekk1phd pages 2-3)
• Filipčík P et al. “A cryptic tubulin-binding domain links MEKK1 to curved tubulin protomers.” PNAS. August 2020. https://doi.org/10.1073/pnas.2006429117. (filipcik2020acryptictubulinbindinga pages 1-2)
• Itah Z et al. “HER2-driven breast cancer suppression by the JNK signaling pathway.” PNAS. January 19, 2023. https://doi.org/10.1073/pnas.2218373120. (itah2023her2drivenbreastcancer pages 1-2, itah2023her2drivenbreastcancer pages 8-10)
• Faridi R et al. “Deafness DFNB128 Associated with a Recessive Variant of Human MAP3K1 Recapitulates Hearing Loss of Map3k1-Deficient Mice.” Genes. June 2024;15:845. https://doi.org/10.3390/genes15070845. (faridi2024deafnessdfnb128associated pages 11-13, faridi2024deafnessdfnb128associated pages 6-8)

References

1. (pham2013map3k1genomicalterations pages 1-3): T. T. Pham, Steven P. Angus, and G. Johnson. Map3k1: genomic alterations in cancer and function in promoting cell survival or apoptosis. Genes & cancer, 4 11-12:419-26, Nov 2013. URL: https://doi.org/10.1177/1947601913513950, doi:10.1177/1947601913513950. This article has 163 citations.

2. (bohlesUnknownyearautoregulationdynamicsof pages 24-28): A Bohles. Auto-regulation dynamics of the mekk1 swim and ring domains. Unknown journal, Unknown year.

3. (lu2002thephddomain pages 2-3): Zhimin Lu, Shuichan Xu, Claudio Joazeiro, Melanie H Cobb, and Tony Hunter. The phd domain of mekk1 acts as an e3 ubiquitin ligase and mediates ubiquitination and degradation of erk1/2. Molecular cell, 9 5:945-56, May 2002. URL: https://doi.org/10.1016/s1097-2765(02)00519-1, doi:10.1016/s1097-2765(02)00519-1. This article has 415 citations and is from a highest quality peer-reviewed journal.

4. (witowsky2003ubiquitylationofmekk1 pages 1-2): James A. Witowsky and Gary L. Johnson. Ubiquitylation of mekk1 inhibits its phosphorylation of mkk1 and mkk4 and activation of the erk1/2 and jnk pathways*. The Journal of Biological Chemistry, 278:1403-1406, Jan 2003. URL: https://doi.org/10.1074/jbc.c200616200, doi:10.1074/jbc.c200616200. This article has 116 citations.

5. (xia2007mekk1mediatesthe pages 1-2): Yan Xia, Ji Wang, Shuichan Xu, Gary L. Johnson, Tony Hunter, and Zhimin Lu. Mekk1 mediates the ubiquitination and degradation of c-jun in response to osmotic stress. Jan 2007. URL: https://doi.org/10.1128/mcb.01355-06, doi:10.1128/mcb.01355-06. This article has 95 citations and is from a domain leading peer-reviewed journal.

6. (charlaftis2014themekk1phd pages 1-2): Nikolaos Charlaftis, Tesha Suddason, Xuefeng Wu, Saba Anwar, Michael Karin, and Ewen Gallagher. The mekk1 phd ubiquitinates tab1 to activate mapks in response to cytokines. The EMBO Journal, 33:2581-2596, Sep 2014. URL: https://doi.org/10.15252/embj.201488351, doi:10.15252/embj.201488351. This article has 58 citations.

7. (bohlesUnknownyearautoregulationdynamicsof pages 28-31): A Bohles. Auto-regulation dynamics of the mekk1 swim and ring domains. Unknown journal, Unknown year.

8. (filipcik2020acryptictubulinbindinga pages 1-2): Pavel Filipčík, Sharissa L. Latham, Antonia L. Cadell, Catherine L. Day, David R. Croucher, and Peter D. Mace. A cryptic tubulin-binding domain links mekk1 to curved tubulin protomers. Proceedings of the National Academy of Sciences of the United States of America, 117:21308-21318, Aug 2020. URL: https://doi.org/10.1073/pnas.2006429117, doi:10.1073/pnas.2006429117. This article has 22 citations and is from a highest quality peer-reviewed journal.

9. (bohlesUnknownyearautoregulationdynamicsofa pages 169-173): A Bohles. Auto-regulation dynamics of the mekk1 swim and ring domains. Unknown journal, Unknown year.

10. (lu2002thephddomain pages 3-5): Zhimin Lu, Shuichan Xu, Claudio Joazeiro, Melanie H Cobb, and Tony Hunter. The phd domain of mekk1 acts as an e3 ubiquitin ligase and mediates ubiquitination and degradation of erk1/2. Molecular cell, 9 5:945-56, May 2002. URL: https://doi.org/10.1016/s1097-2765(02)00519-1, doi:10.1016/s1097-2765(02)00519-1. This article has 415 citations and is from a highest quality peer-reviewed journal.

11. (witowsky2003ubiquitylationofmekk1 pages 2-3): James A. Witowsky and Gary L. Johnson. Ubiquitylation of mekk1 inhibits its phosphorylation of mkk1 and mkk4 and activation of the erk1/2 and jnk pathways*. The Journal of Biological Chemistry, 278:1403-1406, Jan 2003. URL: https://doi.org/10.1074/jbc.c200616200, doi:10.1074/jbc.c200616200. This article has 116 citations.

12. (charlaftis2014themekk1phd pages 2-3): Nikolaos Charlaftis, Tesha Suddason, Xuefeng Wu, Saba Anwar, Michael Karin, and Ewen Gallagher. The mekk1 phd ubiquitinates tab1 to activate mapks in response to cytokines. The EMBO Journal, 33:2581-2596, Sep 2014. URL: https://doi.org/10.15252/embj.201488351, doi:10.15252/embj.201488351. This article has 58 citations.

13. (itah2023her2drivenbreastcancer pages 1-2): Zeynep Itah, Shanzah Chaudhry, Sithara Raju Ponny, Ozkan Aydemir, Alexandra Lee, Julie Cavanagh-Kyros, Cathy Tournier, William J. Muller, and Roger J. Davis. Her2-driven breast cancer suppression by the jnk signaling pathway. Proceedings of the National Academy of Sciences of the United States of America, Jan 2023. URL: https://doi.org/10.1073/pnas.2218373120, doi:10.1073/pnas.2218373120. This article has 35 citations and is from a highest quality peer-reviewed journal.

14. (pham2013map3k1genomicalterations pages 5-7): T. T. Pham, Steven P. Angus, and G. Johnson. Map3k1: genomic alterations in cancer and function in promoting cell survival or apoptosis. Genes & cancer, 4 11-12:419-26, Nov 2013. URL: https://doi.org/10.1177/1947601913513950, doi:10.1177/1947601913513950. This article has 163 citations.

15. (itah2023her2drivenbreastcancer pages 8-10): Zeynep Itah, Shanzah Chaudhry, Sithara Raju Ponny, Ozkan Aydemir, Alexandra Lee, Julie Cavanagh-Kyros, Cathy Tournier, William J. Muller, and Roger J. Davis. Her2-driven breast cancer suppression by the jnk signaling pathway. Proceedings of the National Academy of Sciences of the United States of America, Jan 2023. URL: https://doi.org/10.1073/pnas.2218373120, doi:10.1073/pnas.2218373120. This article has 35 citations and is from a highest quality peer-reviewed journal.

16. (lu2025anovelvariant pages 1-2): Yufu Lu, Sijia Wei, Shuang Wang, Jingzhi Zhang, Yongjie Xu, Changyudong Huang, Wei Pan, and Zhengrong Wang. A novel variant in the map3k1 genomic locus reveals abnormal cell apoptosis as a potential pathogenic mechanism in 46, xy disorders of sex development. Molecular Medicine Reports, 32:1-10, Jun 2025. URL: https://doi.org/10.3892/mmr.2025.13589, doi:10.3892/mmr.2025.13589. This article has 1 citations and is from a peer-reviewed journal.

17. (pham2013map3k1genomicalterations pages 4-5): T. T. Pham, Steven P. Angus, and G. Johnson. Map3k1: genomic alterations in cancer and function in promoting cell survival or apoptosis. Genes & cancer, 4 11-12:419-26, Nov 2013. URL: https://doi.org/10.1177/1947601913513950, doi:10.1177/1947601913513950. This article has 163 citations.

18. (faridi2024deafnessdfnb128associated pages 11-13): Rabia Faridi, Rizwan Yousaf, Sayaka Inagaki, Rafal Olszewski, Shoujun Gu, Robert Morell, Elizabeth Wilson, Ying Xia, Tanveer Qaiser, Muhammad Rashid, Cristina Fenollar-Ferrer, Michael Hoa, Sheikh Riazuddin, and Thomas Friedman. Deafness dfnb128 associated with a recessive variant of human map3k1 recapitulates hearing loss of map3k1-deficient mice. Genes, 15:845, Jun 2024. URL: https://doi.org/10.3390/genes15070845, doi:10.3390/genes15070845. This article has 3 citations.

19. (faridi2024deafnessdfnb128associated pages 10-11): Rabia Faridi, Rizwan Yousaf, Sayaka Inagaki, Rafal Olszewski, Shoujun Gu, Robert Morell, Elizabeth Wilson, Ying Xia, Tanveer Qaiser, Muhammad Rashid, Cristina Fenollar-Ferrer, Michael Hoa, Sheikh Riazuddin, and Thomas Friedman. Deafness dfnb128 associated with a recessive variant of human map3k1 recapitulates hearing loss of map3k1-deficient mice. Genes, 15:845, Jun 2024. URL: https://doi.org/10.3390/genes15070845, doi:10.3390/genes15070845. This article has 3 citations.

20. (faridi2024deafnessdfnb128associated pages 2-4): Rabia Faridi, Rizwan Yousaf, Sayaka Inagaki, Rafal Olszewski, Shoujun Gu, Robert Morell, Elizabeth Wilson, Ying Xia, Tanveer Qaiser, Muhammad Rashid, Cristina Fenollar-Ferrer, Michael Hoa, Sheikh Riazuddin, and Thomas Friedman. Deafness dfnb128 associated with a recessive variant of human map3k1 recapitulates hearing loss of map3k1-deficient mice. Genes, 15:845, Jun 2024. URL: https://doi.org/10.3390/genes15070845, doi:10.3390/genes15070845. This article has 3 citations.

21. (faridi2024deafnessdfnb128associated pages 6-8): Rabia Faridi, Rizwan Yousaf, Sayaka Inagaki, Rafal Olszewski, Shoujun Gu, Robert Morell, Elizabeth Wilson, Ying Xia, Tanveer Qaiser, Muhammad Rashid, Cristina Fenollar-Ferrer, Michael Hoa, Sheikh Riazuddin, and Thomas Friedman. Deafness dfnb128 associated with a recessive variant of human map3k1 recapitulates hearing loss of map3k1-deficient mice. Genes, 15:845, Jun 2024. URL: https://doi.org/10.3390/genes15070845, doi:10.3390/genes15070845. This article has 3 citations.

22. (itah2023her2drivenbreastcancer pages 10-11): Zeynep Itah, Shanzah Chaudhry, Sithara Raju Ponny, Ozkan Aydemir, Alexandra Lee, Julie Cavanagh-Kyros, Cathy Tournier, William J. Muller, and Roger J. Davis. Her2-driven breast cancer suppression by the jnk signaling pathway. Proceedings of the National Academy of Sciences of the United States of America, Jan 2023. URL: https://doi.org/10.1073/pnas.2218373120, doi:10.1073/pnas.2218373120. This article has 35 citations and is from a highest quality peer-reviewed journal.

23. (OpenTargets Search: -MAP3K1): Open Targets Query (-MAP3K1, 27 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

24. (faridi2023deafnessdfnb110associated pages 7-10): Rabia Faridi, Rizwan Yousaf, Sayaka Inagaki, Rafal Olszewski, Shoujun Gu, Robert J. Morell, Elizabeth Wilson, Ying Xia, Tanveer Ahmed Qaiser, Muhammad Rashid, Cristina Fenollar-Ferrer, Michael Hoa, Sheikh Riazuddin, and Thomas B. Friedman. Deafness dfnb110 associated with a human map3k1 recessive variant recapitulates hearing loss of map3k1 kinase deficient mice. Unknown journal, Sep 2023. URL: https://doi.org/10.21203/rs.3.rs-3310464/v1, doi:10.21203/rs.3.rs-3310464/v1.

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Citations

1. filipcik2020acryptictubulinbindinga pages 1-2
2. lu2002thephddomain pages 2-3
3. lu2002thephddomain pages 3-5
4. lu2025anovelvariant pages 1-2
5. Lu et al., Molecular Cell, May 2002; DOI: https://doi.org/10.1016/S1097-2765(02)00519-1
6. Xia et al., Molecular and Cellular Biology, January 2007; DOI: https://doi.org/10.1128/MCB.01355-06
7. Charlaftis et al., EMBO Journal, September 26, 2014; DOI: https://doi.org/10.15252/embj.201488351
8. Witowsky and Johnson, Journal of Biological Chemistry, January 2003; DOI: https://doi.org/10.1074/jbc.C200616200
9. Filipčík et al., PNAS, August 2020; DOI: https://doi.org/10.1073/pnas.2006429117
10. Faridi et al., Genes 15:845, published June 2024; DOI: https://doi.org/10.3390/genes15070845
11. Itah et al., PNAS, published January 19, 2023; DOI: https://doi.org/10.1073/pnas.2218373120
12. https://doi.org/10.1016/S1097-2765(02
13. https://doi.org/10.1128/MCB.01355-06].
14. https://doi.org/10.15252/embj.201488351].
15. https://doi.org/10.1074/jbc.C200616200].
16. https://doi.org/10.1073/pnas.2006429117].
17. https://doi.org/10.3390/genes15070845].
18. https://doi.org/10.1073/pnas.2218373120].
19. https://doi.org/10.1177/1947601913513950.
20. https://doi.org/10.1128/MCB.01355-06.
21. https://doi.org/10.15252/embj.201488351.
22. https://doi.org/10.1073/pnas.2006429117.
23. https://doi.org/10.1073/pnas.2218373120.
24. https://doi.org/10.3390/genes15070845.
25. https://doi.org/10.1177/1947601913513950,
26. https://doi.org/10.1016/s1097-2765(02
27. https://doi.org/10.1074/jbc.c200616200,
28. https://doi.org/10.1128/mcb.01355-06,
29. https://doi.org/10.15252/embj.201488351,
30. https://doi.org/10.1073/pnas.2006429117,
31. https://doi.org/10.1073/pnas.2218373120,
32. https://doi.org/10.3892/mmr.2025.13589,
33. https://doi.org/10.3390/genes15070845,
34. https://doi.org/10.21203/rs.3.rs-3310464/v1,