Alternative titles; symbols
HGNC Approved Gene Symbol: MAPKAPK3
SNOMEDCT: 1187639002;
Cytogenetic location: 3p21.2 Genomic coordinates (GRCh38): 3:50,611,520-50,649,291 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.2 | ?Macular dystrophy, patterned, 3 | 617111 | Autosomal dominant | 3 |
Sithanandam et al. (1996) identified a mitogen-activated protein kinase (MAPK)-activated protein kinase with a single potential SH3-binding site in the proline-rich N terminus, a putative ATP-binding site, 2 MAP kinase phosphorylation site motifs, and a putative nuclear localization signal. They called the protein 3pK. The gene was cloned from NotI linking clones and codes for a 2.5-kd mRNA that was expressed in all human tissues examined, being especially high in the heart and skeletal muscle. Sequence analysis revealed a 382-amino acid protein of 42 kD. It shares 72% nucleotide and 75% amino acid identity with MAPKAP kinase-2 (602006). In HL60 cells and transiently transfected HEK293 cells, activation of 3pK in vivo by the growth inducers serum and tetradecanoyl phorbol acetate was Raf dependent and was mediated by the Raf/MEK/ERK kinase cascade.
Using RT-qPCR, Meunier et al. (2016) confirmed that MAPKAPK3 mRNA is found in the retinal pigment epithelium (RPE) derived from human induced pluripotent stem cells. In addition, they observed that relative expression of MAPKAPK3 compared with MAPKAPK2 (602006) was proprtionally higher in the RPE than in fibroblasts, suggesting that MAPKAPK3 is critical for RPE physiology.
Maizels et al. (2001) determined that the MAPKAPK3 gene contains 10 exons.
Maizels et al. (2001) mapped the MAPKAPK3 gene to chromosome 3p21.3.
Ludwig et al. (1996) showed that 3pK is the first kinase to be activated through all 3 MAPK cascades: extracellular signal-regulated kinase (ERK; see 176948), MAPKAP kinase-2, and Jun-N-terminal kinases/stress-activated protein kinases. They showed also that 3pK has a novel substrate specificity from other MAPKAPs. Thus, Ludwig et al. (1996) concluded that 3pK functions as an integrative element of signaling in both mitogen and stress responses.
Maizels et al. (2001) investigated the activation in vivo and regulation of the expression of components of the p38 MAPK (600289) pathway during gonadotropin-induced formation and development of the rat corpus luteum. They postulated that the p38 MAPK pathway could serve to promote phosphorylation of key substrates during luteal maturation, since maturing luteal cells, thought to be cAMP-nonresponsive, nevertheless maintain critical phosphoproteins. The p38 MAPK downstream protein kinase target MAPKAPK3 was newly induced at both mRNA and protein levels during luteal formation and maturation, while mRNA and protein expression of the closely related MAPKAPK2 diminished. MAPKAPK3-specific immune complex kinase assays provided direct evidence that MAPKAPK3 was in an activated state during luteal maturation in vivo. Transient transfection studies provided direct evidence that MAPKAPK3 was capable of signaling to activate CREB (123810) transcriptional activity, as assessed by means of GAL4-CREB fusion protein construct coexpressed with GAL4-luciferase reporter construct. Introduction of wildtype, but not kinase-dead mutant, MAPKAPK3 cDNA, into a mouse ovarian cell line stimulated GAL4-CREB-dependent transcriptional activity approximately 3-fold. Maizels et al. (2001) concluded that MAPKAPK3 is uniquely poised to support luteal maturation through the phosphorylation and activation of the nuclear transcription factor CREB.
In a 3-generation family from Martinique with patterned macular dystrophy-3 (MDPT3; 617111), Meunier et al. (2016) identified heterozygosity for a missense mutation in the MAPKAPK3 gene (L173P; 602130.0001) that segregated with disease and was not found in controls. Functional analysis demonstrated mislocalization of the mutant protein in the cytoplasm, resulting in alteration of the cytoskeleton.
Meunier et al. (2016) performed electron microscopy of eyes from Mapkapk3 -/- mice and observed abnormal thickening and thinning of the Bruch membrane that progressed with age up to 6 months. At 6 months, the mutant mice had no additional retinal lesion and no photoreceptor loss compared to wildtype littermates.
In 14 affected members over 3 generations of a large family from Martinique with patterned macular dystrophy-3 (MDPT3; 617111), Meunier et al. (2016) identified heterozygosity for a c.518T-C transition (c.518T-C, ENST00000446044) in exon 8 of the MAPKAPK3 gene, resulting in a leu173-to-pro (L173P) substitution at a conserved residue. The mutation was not found in 27 asymptomatic family members or in 140 control alleles from Martinique individuals over 40 years of age, or in the 1000 Genomes Project, Exome Variant Server, dbSNP (12/5/2005) or ExAC (12/5/2005) databases. The mutation was present in 1 asymptomatic family member, a 21-year-old woman who inherited it from her affected father and who was likely in the preclinical stage of the disease. Functional analysis in HEK cells showed that the wildtype protein was mostly localized in the nucleus, whereas the mutant was predominantly localized in the cytoplasm. In addition, more than 30% of cells transfected with the mutant allele were multinucleated, compared with only 8% of wildtype cells, indicating that expression of the mutant results in inhibition of cytokinesis. Structural analysis of the tubulin-related cytoskeleton revealed severe depolarization of tubulin structures, and no colocalization of microtubules with mutant MAPKAPK3 was detected in transfected cells. Meunier et al. (2016) suggested that mislocalization of the mutant protein could cause nuclear MAPKAPK3 haploinsufficiency and that the L173P mutant could alter the cytoskeleton by a deleterious cytoplasmic gain of function.
Jean-Charles, A., Cohen, S. Y., Merle, H., Quentel, G., Legargasson, J.-F., Guadric, A. Martinique (West Indies) crinkled retinal pigment epitheliopathy: clinical description. Retina 33: 1041-1048, 2013. [PubMed: 23370609] [Full Text: https://doi.org/10.1097/IAE.0b013e3182733ff3]
Ludwig, S., Engel, K., Hoffmeyer, A., Sithanandam, G., Neufeld, B., Palm, D., Gaestel, M., Rapp, U. 3pK, a novel mitogen-activated protein (MAP) kinase-activated protein kinase, is targeted by three MAP kinase pathways. Molec. Cell. Biol. 16: 6687-6697, 1996. [PubMed: 8943323] [Full Text: https://doi.org/10.1128/MCB.16.12.6687]
Maizels, E. T., Mukherjee, A., Sithanandam, G., Peters, C. A., Cottom, J., Mayo, K. E., Hunzicker-Dunn, M. Developmental regulation of mitogen-activated protein kinase-activated kinases-2 and -3 (MAPKAPK-2/-3) in vivo during corpus luteum formation in the rat. Molec. Endocr. 15: 716-733, 2001. [PubMed: 11328854] [Full Text: https://doi.org/10.1210/mend.15.5.0634]
Meunier, I., Lenaers, G., Bocquet, B., Baudoin, C., Piro-Megy, C., Cubizolle, A., Quiles, M., Jean-Charles, A., Cohen, S. Y., Merle, H., Gaudric, A., Labesse, G., and 9 others. A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium. Hum. Molec. Genet. 25: 916-926, 2016. [PubMed: 26744326] [Full Text: https://doi.org/10.1093/hmg/ddv624]
Sithanandam, G., Latif, F., Duh, F.-M., Bernal, R., Smola, U., Li, H., Kuzmin, I., Wixler, V., Geil, L., Shrestha, S., Lloyd, P., Bader, S., Sekido, Y., Tartof, K. D., Kashuba, V. I., Zabarovsky, E. R., Dean, M., Klein, G., Lerman, M. I., Minna, J. D., Rapp, U. R., Allikmets, R. 3pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene region. Molec. Cell. Biol. 16: 868-876, 1996. Note: Erratum: Molec. Cell. Biol. 16: 1880 only, 1996. [PubMed: 8622688] [Full Text: https://doi.org/10.1128/MCB.16.3.868]