MAP3K3 gene [Neurosurgery Wiki]

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====== MAP3K3 gene ======


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

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.

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.[6] MEKK3 regulates the p38, JNK and ERK1/2 pathways.
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[[Cerebral Cavernous Malformation]] CCMs arise due to loss of function in one of the genes that encode the CCM complex, a negative regulator of [[MEKK3]]-[[KLF2]]/4 signaling in [[vascular]] [[endothelial cell]]s. Gain-of-function mutations in [[PIK3CA]] (encoding the enzymatic subunit of the [[PI3K]] (phosphoinositide 3-kinase) pathway associated with cell growth) synergize with CCM gene loss-of-function to generate rapidly growing lesions
((Li L, Ren AA, Gao S, Su YS, Yang J, Bockman J, Mericko-Ishizuka P, Griffin J, Shenkar R, Alcazar R, Moore T, Lightle R, DeBiasse D, Awad IA, Marchuk DA, Kahn ML, Burkhardt JK. mTORC1 Inhibitor Rapamycin Inhibits Growth of Cerebral Cavernous Malformation in Adult Mice. Stroke. 2023 Sep 25. doi: 10.1161/STROKEAHA.123.044108. Epub ahead of print. PMID: 37746705.)).
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Ren et al. analyzed 290 surgical [[specimen]]s from symptomatic CCM patients, utilizing [[whole-exome sequencing]], droplet digital PCR, and targeted panel sequencing, alongside [[immunohistology]] to examine genotypic and phenotypic differences. Among 290 cases, 201 had somatic [[MAP3K3]], [[PIK3CA]], or [[germline]] CCM mutations, each associated with distinct clinical [[parameter]]s: [[hemorrhage]] [[risk]] (P < 0.001), [[lesion]] size (P = 0.019), non-hemorrhagic [[epilepsy]] (P < 0.001), Zabramski classifications (P < 0.001), [[developmental venous anomaly]] presence (P < 0.001), and MRI-detected [[edema]] (P < 0.001). [[PIK3CA]] mutations showed a higher hemorrhage risk than MAP3K3 and combined MAP3K3 & PIK3CA mutations (P < 0.001). Within PIK3CA mutations, the p.H1047R variant correlated with higher bleeding risk than p.E545K (P = 0.007). For non-hemorrhagic epilepsy, patients with single MAP3K3 mutations or combined MAP3K3 & PIK3CA mutations were at greater risk than those with PIK3CA mutations alone. Histopathologically, lesions with PIK3CA mutations displayed cyst walls, pS6-positive dilated capillaries, and fresh blood cells, while MAP3K3 and double mutation lesions exhibited classic CCM pathology with SMA-positive and KLF4-positive vessels, collagen, and calcification. PIK3CA lesions had fewer KLF4-positive cells than double mutations lesions (P < 0.001), and EndMT (SMA-positive) cells compared to double mutation lesions (P < 0.05) and MAP3K3 mutations (P < 0.001), with more pS6 compared to MAP3K3 mutations (P < 0.05). This study underscores the diverse clinical, genomic, and histopathological characteristics in CCMs, suggesting potential predictive markers based on mutation subtypes and MRI features
((Ren J, Wang D, Wang L, Jiang C, Tian A, Cui Z, Ren Y, Bian L, Zeng G, Meng G, Shan Y, Liang J, Xiao X, Tang J, Wei Y, He C, Sun L, Ma Y, Yu J, Li G, Ye M, Hu P, Li J, Li Y, Niu L, Li Q, Ling F, Burkhardt JK, Zhang H, Hong T. Clinical, genomic, and histopathologic diversity in [[cerebral cavernous malformation]]s. Acta Neuropathol Commun. 2025 Feb 5;13(1):23. doi: 10.1186/s40478-025-01940-1. PMID: 39910686.)).
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Ren et al. present a compelling study linking genotypic variations in [[cerebral cavernous malformation]]s to clinical, histopathological, and imaging [[feature]]s. The [[study]] provides valuable predictive markers for hemorrhage risk and epilepsy but would benefit from functional [[validation]] and broader [[cohort]] inclusion. Future studies should investigate the therapeutic potential of targeting the [[PI3K]] and [[MAP3K3]] pathways in CCMs, integrating longitudinal patient data to refine [[risk assessment]] and treatment strategies.