Q60929 (MEF2A_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 124. History...
Names and origin
|Protein names||Recommended name:|
Myocyte-specific enhancer factor 2A
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||498 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Transcriptional activator which binds specifically to the MEF2 element, 5'-YTA[AT]4TAR-3', found in numerous muscle-specific genes. Also involved in the activation of numerous growth factor- and stress-induced genes. Mediates cellular functions not only in skeletal and cardiac muscle development, but also in neuronal differentiation and survival. Plays diverse roles in the control of cell growth, survival and apoptosis via p38 MAPK signaling in muscle-specific and/or growth factor-related transcription. In cerebellar granule neurons, phosphorylated and sumoylated MEF2A represses transcription of NUR77 promoting synaptic differentiation. Associates with chromatin to the ZNF16 promoter By similarity.
Binds DNA as a homo- or heterodimer. Dimerizes with MEF2D. Interacts with HDAC7. Interacts with PIAS1; the interaction enhances sumoylation. Interacts with HDAC4, HDAC9 and SLC2A4RG. Interacts (via the N-terminal) with MAPK7; the interaction results in the phosphorylation and transcriptional activity of MEF2A By similarity. Ref.4 Ref.6
Widely expressed though mainly restricted to skeletal and cardiac muscle, brain, neurons and lymphocytes. Differentially expressed depending on if isoforms contain the beta domain or not, with the total expression of the beta domain-lacking isoforms vastly exceding that of the beta domain-containing isoforms. Isoforms containing the beta domain are expressed primarily in skeletal and cardiac muscle and in brain. Also present in lung and testis. Splicing to include the beta domain is induced in differentiating myocytes. Isoforms lacking the beta domain are expressed less abundantly in skeletal muscle, brain and lymphocytes, and are uniquely found in ovary, liver, spleen and kidney. In embryos, the beta domain-containing and beta domain-lacking isoforms are equally expressed. Also expressed cerebellar granule neurons and other regions of the CNS. Highest levels in the olfactory bulb, cortex, hippocampus, thalamus and cerebellum. Ref.1 Ref.5
In the developing cerebellum, increasing levels after birth. The majority of this increase occurs around postnataL day 9 reaching a peak at postnatal day 15-18 which is maintained in adults. Ref.1
The beta domain, missing in a number of isoforms, is required for enhancement of transcriptional activity By similarity.
Constitutive phosphorylation on Ser-406 promotes Lys-401 sumoylation thus preventing acetylation at this site. Dephosphorylation on Ser-406 by PPP3CA upon neuron depolarization promotes a switch from sumoylation to acetylation on residue Lys-403 leading to inhibition of dendrite claw differentiation. Phosphorylation on Thr-312 and Thr-319 are the main sites involved in p38 MAPK signaling and activate transcription. Phosphorylated on these sites by MAPK14/p38alpha and MAPK11/p38beta, but not by MAPK13/p38delta nor by MAPK12/p38gamma. Phosphorylation on Ser-408 by CDK5 induced by neurotoxicity inhibits MEF2A transcriptional activation leading to apoptosis of cortical neurons. Phosphorylation on Thr-312, Thr-319 and Ser-355 can be induced by EGF By similarity. Isoform 3 is phosphorylated on Ser-98 and Thr-108. Ref.6
Sumoylation on Lys-401 is enhanced by PIAS1 and represses transcriptional activity. Phosphorylation on Ser-406 is required for sumoylation. Has no effect on nuclear location nor on DNA binding. Sumoylated with SUMO1 and, to a lesser extent with SUMO2 and SUMO3. PIASx facilitates sumoylation in postsynaptic dendrites in the cerebellar cortex and promotes their morphogenesis By similarity.
Acetylation on Lys-401 activates transcriptional activity. Acetylated by p300 on several sites in diffentiating myocytes. Acetylation on Lys-4 increases DNA binding and transactivation. Hyperacetylation by p300 leads to enhanced cardiac myocyte growth and heart failure By similarity.
Proteolytically cleaved in cerebellar granule neurons on several sites by caspase 3 and caspase 7 following neurotoxicity. Preferentially cleaves the CDK5-mediated hyperphosphorylated form which leads to neuron apoptosis and transcriptional inactivation By similarity. Ref.6
Belongs to the MEF2 family.
Contains 1 MADS-box domain.
Contains 1 Mef2-type DNA-binding domain.
|This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1 (identifier: Q60929-1) |
This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
|Isoform 2 (identifier: Q60929-2) |
The sequence of this isoform differs from the canonical sequence as follows:
|Isoform 3 (identifier: Q60929-3) |
The sequence of this isoform differs from the canonical sequence as follows:
87-130: TLRKKGLNGC...DSDFIFKRGP → ALNKKEHRGC...DNMMRNHKIA
|Note: Contains a phosphoserine at position 98. Contains a phosphothreonine at position 108.|
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 498||498||Myocyte-specific enhancer factor 2A||PRO_0000199429|
|Domain||3 – 57||55||MADS-box|
|DNA binding||58 – 86||29||Mef2-type Potential|
|Region||264 – 281||18||Required for interaction with MAPKs By similarity|
|Region||287 – 294||8||Beta domain By similarity|
|Compositional bias||254 – 257||4||Poly-Pro|
|Compositional bias||288 – 293||6||Poly-Glu|
|Compositional bias||418 – 439||22||Gln/Pro-rich|
|Compositional bias||448 – 455||8||Poly-Ser|
|Site||174 – 175||2||Cleavage Probable|
|Site||211 – 212||2||Cleavage Probable|
|Site||457 – 458||2||Cleavage Probable|
Amino acid modifications
|Modified residue||59||1||Phosphoserine; by CK2 By similarity|
|Modified residue||98||1||Phosphoserine By similarity|
|Modified residue||233||1||Phosphoserine By similarity|
|Modified residue||247||1||N6-acetyllysine Ref.8|
|Modified residue||253||1||Phosphoserine By similarity|
|Modified residue||310||1||Phosphothreonine; by MAPK7; alternate By similarity|
|Modified residue||310||1||Phosphothreonine; by NLK; alternate Ref.6|
|Modified residue||317||1||Phosphothreonine; by MAPK7 By similarity|
|Modified residue||353||1||Phosphoserine; by MAPK7 By similarity|
|Modified residue||401||1||N6-acetyllysine; alternate By similarity|
|Modified residue||406||1||Phosphoserine By similarity|
|Modified residue||444||1||Phosphoserine By similarity|
|Cross-link||401||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO); alternate By similarity|
|Alternative sequence||87 – 130||44||TLRKK…FKRGP → ALNKKEHRGCDSPDPDTSYV LTPHTEEKYKKINEEFDNMM RNHKIA in isoform 3.||VSP_026060|
|Alternative sequence||287 – 294||8||Missing in isoform 2 and isoform 3.||VSP_026031|
|Sequence conflict||98||1||S → N in AAA74030. Ref.1|
|Sequence conflict||116||1||S → I in AAA74030. Ref.1|
|Sequence conflict||133||1||L → F in AAA74030. Ref.1|
|Sequence conflict||151||1||A → P in AAA74030. Ref.1|
|Sequence conflict||154||1||Y → D in AAA74030. Ref.1|
|Sequence conflict||174 – 175||2||DS → ET in AAA74030. Ref.1|
|Sequence conflict||201||1||G → S in BAE21297. Ref.2|
|Sequence conflict||274||1||V → A in AAA74030. Ref.1|
|Sequence conflict||367||1||Q → E in AAA74030. Ref.1|
|Sequence conflict||373 – 374||2||AA → TT in AAA74030. Ref.1|
|Sequence conflict||419 – 423||5||QQQQQ → HHHHH in AAA74030. Ref.1|
|Sequence conflict||478||1||P → A in AAA74030. Ref.1|
|||"The expression of MEF2 genes is implicated in CNS neuronal differentiation."|
Lin X., Shah S., Bulleit R.F.
Brain Res. Mol. Brain Res. 42:307-316(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
|||"The transcriptional landscape of the mammalian genome."|
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
|||"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."|
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
Tissue: Brain and Mammary tumor.
|||"Mechanism for nucleocytoplasmic shuttling of histone deacetylase 7."|
Kao H.-Y., Verdel A., Tsai C.-C., Simon C., Juguilon H., Khochbin S.
J. Biol. Chem. 276:47496-47507(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH HDAC7.
|||"Alternative pre-mRNA splicing governs expression of a conserved acidic transactivation domain in myocyte enhancer factor 2 factors of striated muscle and brain."|
Zhu B., Ramachandran B., Gulick T.
J. Biol. Chem. 280:28749-28760(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY OF ISOFORMS.
|||"Nemo-like kinase-myocyte enhancer factor 2A signaling regulates anterior formation in Xenopus development."|
Satoh K., Ohnishi J., Sato A., Takeyama M., Iemura S., Natsume T., Shibuya H.
Mol. Cell. Biol. 27:7623-7630(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NLK, PHOSPHORYLATION AT THR-310.
|||"Large-scale phosphorylation analysis of mouse liver."|
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-98 AND THR-108 (ISOFORM 3), IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
|||"SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways."|
Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y., Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.
Mol. Cell 50:919-930(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-247, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Embryonic fibroblast.
|+||Additional computationally mapped references.|
|Accession||Primary (citable) accession number: Q60929|
Secondary accession number(s): Q3V155, Q4VA09, Q6P8Q3
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|