Affinage

MYL12A

Myosin regulatory light chain 12A · UniProt P19105

Length
171 aa
Mass
19.8 kDa
Annotated
2026-06-10
37 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MYL12A is a non-muscle myosin II regulatory light chain that maintains the integrity of the actomyosin contractile machinery: it associates with the non-muscle myosin heavy chains MYH9 and MYH10 and the essential light chain MYL6, and its depletion both destabilizes these myosin II subunits and produces marked changes in cell morphology and dynamics (PMID:21126233). Its contractile output is gated by phosphorylation at the conserved Thr18/Ser19 (Thr20/Ser19) regulatory site — by smooth muscle myosin light chain kinase and by the bacterial effector kinase SteC — which drives actin rearrangement and cell-shape changes, with MYL12A playing a dominant role among regulatory light chain isoforms in supporting cell spreading (PMID:38528181, PMID:33877471, PMID:26663899). In the cochlea this phosphorylation-driven actomyosin activity tunes hair-bundle stiffness and the operating point of mechanotransduction (PMID:40240732). MYL12A protein abundance is set post-translationally: it is stabilized by necdin acting through the SGT1–HSP90 chaperone system, a function required for cardiac contractility, and it is protected from proteasomal turnover by OTUD3-mediated deubiquitination (PMID:38832028, PMID:39097608). Beyond its cytoskeletal role, MYL12A serves as a cytoplasmic retention factor for the transcriptional regulator AATF, with genotoxic-stress-induced MK2 phosphorylation of AATF dissolving the complex to release AATF for nuclear repression of pro-apoptotic genes (PMID:22909821, PMID:22983126).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2011 High

    Established that non-muscle regulatory light chains are not merely accessory but are structurally required to hold the myosin II holoenzyme together, answering whether RLCs maintain heavy-chain stability.

    Evidence Reciprocal Co-IP plus siRNA knockdown with quantitative western blot and morphological phenotyping in NIH 3T3 fibroblasts

    PMID:21126233

    Open questions at the time
    • Does not distinguish the non-redundant contributions of MYL12A versus MYL12B
    • Mechanism of heavy-chain destabilization upon RLC loss not resolved
  2. 2012 Medium

    Revealed a non-cytoskeletal moonlighting role: MYL12A sequesters the transcription factor AATF in the cytoplasm, and stress-dependent MK2 phosphorylation of AATF releases it to repress p53 pro-apoptotic targets, linking MYL12A to the DNA damage response.

    Evidence Co-IP, subcellular fractionation, phospho-mimetic mutants, kinase-inhibitor epistasis, and xenograft experiments

    PMID:22909821 PMID:22983126

    Open questions at the time
    • Whether AATF binding is to phosphorylated or unphosphorylated MYL12A is unclear
    • Structural basis of the MYL12A:AATF interaction undefined
    • Relationship between AATF sequestration and myosin II assembly not addressed
  3. 2015 Medium

    Defined MYL12A as the dominant regulatory light chain isoform for cell spreading and confirmed Thr18/Ser19 phosphorylation, distinguishing functional roles among the three MRLC isoforms.

    Evidence siRNA depletion of all MRLCs with single-isoform rescue, phospho-Thr18/Ser19 western blot, and FRAP turnover analysis in HeLa cells

    PMID:26663899

    Open questions at the time
    • Molecular basis for MYL12A dominance over MRLC1 not identified
    • Does not map which spreading pathways require MYL12A specifically
  4. 2021 Medium

    Showed that smMLCK-dependent MYL12 phosphorylation drives apical-constriction-like shape changes in cochlear hair cells, extending the phospho-regulatory mechanism to a sensory-cell context.

    Evidence In vitro kinase assay with purified protein, ddPCR expression, immunofluorescence, and ML-7 pharmacological inhibition with morphometry

    PMID:33877471

    Open questions at the time
    • ML-7 is not MYL12A-specific, leaving other kinase targets possible
    • Direct contractile consequence in the hair cell not measured at single-molecule level
  5. 2024 Medium

    Identified two post-translational stability controls for MYL12A protein levels — chaperone-mediated stabilization via necdin/SGT1-HSP90 and protection from proteasomal degradation by OTUD3 deubiquitination — tying MYL12A abundance to cardiac contractility and to B-cell lymphoma survival.

    Evidence Yeast two-hybrid, Co-IP, zebrafish morpholino and mouse cardiac overexpression rescue (necdin); deubiquitinase assay, Co-IP, and rupatadine inhibition with viability assays (OTUD3)

    PMID:38832028 PMID:39097608

    Open questions at the time
    • The E3 ligase that ubiquitinates MYL12A is not identified
    • How chaperone stabilization and deubiquitination intersect is unknown
    • Whether these controls regulate myosin II assembly directly is untested
  6. 2024 High

    Demonstrated that a bacterial effector kinase, SteC, directly hijacks MYL12A by phosphorylating Ser19/Thr20 to remodel host actin and breach the gut-vascular barrier, revealing the regulatory site as a target of pathogen subversion.

    Evidence In vitro kinase assays mapping phospho-residues, SteC crystal structure, macrophage migration/invasion assays, and in vivo Salmonella infection model

    PMID:38528181

    Open questions at the time
    • Whether SteC phosphorylation mimics or exceeds physiological MLCK signaling is not quantified
    • Downstream actomyosin contractile changes not structurally resolved
  7. 2025 Medium

    Linked MYL12A-containing actomyosin in hair bundles directly to mechanotransduction physiology, showing it sets bundle stiffness and the resting operating point of transduction channels.

    Evidence Immunostaining localization, NM2/MLCK pharmacological inhibition, stiffness and spontaneous oscillation recordings, transduction channel open-probability measurement, and auditory brainstem response in mice

    PMID:40240732

    Open questions at the time
    • Pharmacology cannot isolate MYL12A from other RLC isoforms
    • Direct phosphorylation state of bundle MYL12A during oscillation not measured

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MYL12A's distinct roles — myosin II structural stabilization, cytoplasmic AATF sequestration, and chaperone/ubiquitin-regulated abundance — are coordinated within a single cell remains unresolved.
  • No integrated model linking phosphorylation, stability control, and the AATF moonlighting function
  • No structure of MYL12A bound to either heavy chains or AATF in the timeline

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0140313 molecular sequestering activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-397014 Muscle contraction 2 R-HSA-5357801 Programmed Cell Death 2
Partners
AATFMYH10MYH9MYL6NECDINOTUD3SDC2STEC
Complex memberships
non-muscle myosin II

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 MYL12A (and MYL12B) associate with non-muscle myosin heavy chains MYH9 (NMHC IIA) and MYH10 (NMHC IIB), and the essential light chain MYL6, in NIH 3T3 fibroblasts. Knockdown of MYL12A/MYL12B causes striking changes in cell morphology and dynamics, and significantly reduces the protein levels of MYH9, MYH10, and MYL6, establishing that non-muscle RLCs are required to maintain the stability/integrity of myosin II. Proteomic co-immunoprecipitation (Co-IP) / proteomic association analysis; siRNA knockdown with morphological phenotyping and quantitative western blot in NIH 3T3 fibroblasts The Biochemical journal High 21126233
2024 The Salmonella effector kinase SteC directly recruits host MYL12A (Myl12a) and phosphorylates its Ser19 and Thr20 residues, causing actin rearrangement and enhanced migration/invasion of macrophages. Crystal structure of SteC revealed an atypical dimerization-mediated catalytic mechanism, and SteC can use a wide range of NTPs (not only ATP) to phosphorylate MYL12A. This phosphorylation is required for Salmonella to breach the gut-vascular barrier in vivo. Biochemical kinase assay (phosphorylation at defined residues), crystal structure determination, in vivo infection model, macrophage migration/invasion assays, site-directed mutagenesis (implicit in residue mapping) The EMBO journal High 38528181
2012 MYL12A (as MRLC3) forms a cytoplasmic complex with the transcriptional regulator AATF. Upon genotoxic stress, MK2-mediated phosphorylation of AATF disrupts the cytoplasmic MRLC3:AATF complex, allowing AATF to translocate to the nucleus where it represses pro-apoptotic p53 target genes (PUMA, BAX, BAK). Thus MYL12A acts as a cytoplasmic retention factor for AATF in the DNA damage response. Co-immunoprecipitation, subcellular fractionation, phospho-mimetic mutant expression, xenograft experiments The EMBO journal Medium 22909821
2012 The cytoplasmic MRLC3 (MYL12A):AATF complex is disrupted by p38MAPK/MK2-mediated phosphorylation of AATF, enabling rapid nuclear AATF localization. This places MYL12A as a component of the p38/MK2/AATF signaling module that represses p53-driven apoptosis. Biochemical epistasis (kinase inhibitor and phospho-mimetic studies), co-immunoprecipitation, nuclear localization assays Cell cycle (Georgetown, Tex.) Medium 22983126
2021 MYL12A (MYL12) is phosphorylated by smooth muscle myosin light chain kinase (smMLCK) in cochlear hair cells. Purified MYL12B was phosphorylated by smMLCK in vitro, and inhibition of smMLCK by ML-7 reduced MYL12 phosphorylation in outer hair cells and was accompanied by expansion of cell area, establishing that MYL12 phosphorylation by smMLCK drives apical constriction-like cellular shape changes in hair cells. In vitro phosphorylation assay with purified protein; ddPCR expression analysis; immunofluorescence; pharmacological inhibition (ML-7) with morphometric readout Journal of the Association for Research in Otolaryngology : JARO Medium 33877471
2024 Necdin interacts with non-muscle myosin regulatory light chain MYL12A/B (identified by yeast two-hybrid screening) and stabilizes MYL12A/B protein via the SGT1-HSP90 chaperone machinery. Loss of necdin leads to reduced MYL12A/B levels and cardiac contractility defects; cardiac-specific overexpression of MYL12A rescued heart dysfunction in necdin-deficient mice. Yeast two-hybrid screening; co-immunoprecipitation; zebrafish morpholino knockdown of MYL12.1; cardiac-specific overexpression rescue in mouse; biochemical chaperone pathway analysis iScience Medium 38832028
2015 MYL12A (MRLC3) is phosphorylated at Thr18/Ser19 in HeLa cells, consistent with myosin II stimulation. Among the three MRLC isoforms, overproduction of MRLC2 or MRLC3 (MYL12A), but not MRLC1, could rescue defective cell spreading caused by depletion of all MRLCs, indicating that MYL12A plays a dominant role in cell spreading. siRNA depletion of all MRLC isoforms; rescue by individual isoform overexpression; western blot for phospho-Thr18/Ser19; FRAP (turnover analysis); computational 3D protein modeling Cytoskeleton (Hoboken, N.J.) Medium 26663899
2024 OTUD3, a deubiquitinase, directly deubiquitinates MYL12A, enhancing cell survival in diffuse large B-cell lymphoma (DLBCL). Inhibition by rupatadine reduces OTUD3-mediated deubiquitination of MYL12A, implicating ubiquitin-mediated proteasomal regulation of MYL12A protein stability. Deubiquitinase activity assay; co-immunoprecipitation; pharmacological inhibition with rupatadine; cell viability assays Cell death & disease Medium 39097608
2025 Non-muscle myosin II (NM2A) and MYL12A are expressed in hair bundles of frog saccular hair cells (confirmed by immunostaining). Pharmacological inhibition of NM2 or MLCK reduces hair bundle stiffness, inhibits spontaneous oscillation, and increases resting open probability of transduction channels, demonstrating that MYL12A-containing actomyosin regulates the mechanical properties and physiological operating point of hair bundles. Immunostaining (localization); NM2/MLCK pharmacological inhibition; hair bundle stiffness measurements; spontaneous oscillation recording; transduction channel open-probability measurement; auditory brainstem response in mice Journal of the Association for Research in Otolaryngology : JARO Medium 40240732
2020 MYL12A was identified as a novel interaction partner of cardiac syndecan-2 by affinity purification/mass spectrometry and verified by co-immunoprecipitation in HEK293 cells, placing MYL12A in a cytoskeletal remodeling network associated with the syndecan-2 interactome. Affinity purification-mass spectrometry (AP-MS); co-immunoprecipitation in HEK293 cells Frontiers in cell and developmental biology Low 32984315

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Myosin regulatory light chains are required to maintain the stability of myosin II and cellular integrity. The Biochemical journal 106 21126233
2002 Molecular cloning and characterization of an ML-236B (compactin) biosynthetic gene cluster in Penicillium citrinum. Molecular genetics and genomics : MGG 101 12172803
2012 AATF/Che-1 acts as a phosphorylation-dependent molecular modulator to repress p53-driven apoptosis. The EMBO journal 51 22909821
2020 The Progression of Acute Myeloid Leukemia from First Diagnosis to Chemoresistant Relapse: A Comparison of Proteomic and Phosphoproteomic Profiles. Cancers 42 32512867
2016 Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans. Human molecular genetics 31 27577874
2006 Thirteen is enough: the myosins of Dictyostelium discoideum and their light chains. BMC genomics 28 16857047
2021 Modeling multi-species RNA modification through multi-task curriculum learning. Nucleic acids research 27 33744973
2015 The Plasmodium Class XIV Myosin, MyoB, Has a Distinct Subcellular Location in Invasive and Motile Stages of the Malaria Parasite and an Unusual Light Chain. The Journal of biological chemistry 27 25802338
2018 Integrated analysis of lncRNA-mRNA co-expression networks in the α-particle induced carcinogenesis of human branchial epithelial cells. International journal of radiation biology 23 30395764
2024 Salmonella manipulates macrophage migration via SteC-mediated myosin light chain activation to penetrate the gut-vascular barrier. The EMBO journal 21 38528181
2004 Dissecting the genetics of human high myopia: a molecular biologic approach. Transactions of the American Ophthalmological Society 21 15747770
2021 Novel partners of USP6 gene in a spectrum of bone and soft tissue lesions. Virchows Archiv : an international journal of pathology 19 33558945
2022 Global Proteomic Analyses Reveals Abnormal Immune Regulation in Patients With New Onset Ankylosing Spondylitis. Frontiers in immunology 17 35371008
2012 Putting the brakes on p53-driven apoptosis. Cell cycle (Georgetown, Tex.) 17 22983126
2006 Identification and characterization of an 8-kDa light chain associated with Dictyostelium discoideum MyoB, a class I myosin. The Journal of biological chemistry 17 16415352
2020 Ligand Binding to the Collagen VI Receptor Triggers a Talin-to-RhoA Switch that Regulates Receptor Endocytosis. Developmental cell 16 32428455
2018 Identification and expression of carbonic anhydrase 2, myosin regulatory light chain 2 and selenium-binding protein 1 in zebrafish Danio rerio: Implication for age-related biomarkers. Gene expression patterns : GEP 11 29738878
2015 Identification of phosphorylated MYL12B as a potential plasma biomarker for septic acute kidney injury using a quantitative proteomic approach. International journal of clinical and experimental pathology 11 26823757
2011 Identification of calmodulin and MlcC as light chains for Dictyostelium myosin-I isozymes. Biochemistry 11 21671662
2024 Rupatadine-inhibited OTUD3 promotes DLBCL progression and immune evasion through deubiquitinating MYL12A and PD-L1. Cell death & disease 9 39097608
2021 Phosphorylation of MYL12 by Myosin Light Chain Kinase Regulates Cellular Shape Changes in Cochlear Hair Cells. Journal of the Association for Research in Otolaryngology : JARO 7 33877471
2020 The Cardiac Syndecan-2 Interactome. Frontiers in cell and developmental biology 7 32984315
2023 Screening core genes and signaling pathways after SFTSV infection by integrated transcriptome profiling analysis. Virus research 6 37211158
2016 Common and differentially expressed long noncoding RNAs for the characterization of high and low grade bladder cancer. Gene 6 27451077
2014 [Overexpression of LaeA enhances mevastatin production and reduces sporulation of Penicillium citrinum]. Wei sheng wu xue bao = Acta microbiologica Sinica 6 25876329
2012 Surface CD3 expression proceeds through both myosin regulatory light chain 9 (MYL9)-dependent and MYL9-independent pathways in Jurkat cells. Journal of smooth muscle research = Nihon Heikatsukin Gakkai kikanshi 6 23538510
2015 Characterization of myosin II regulatory light chain isoforms in HeLa cells. Cytoskeleton (Hoboken, N.J.) 5 26663899
2022 To detect potential pathways and target genes in infantile Pompe patients using computational analysis. BioImpacts : BI 4 35411297
2021 Characterizing RNA Pseudouridylation by Convolutional Neural Networks. Genomics, proteomics & bioinformatics 4 33631424
2020 Proteomics reveals region-specific hemostatic alterations in response to mechanical ventilation in a preterm lamb model of lung injury. Thrombosis research 4 33075590
2014 Structure of the small Dictyostelium discoideum myosin light chain MlcB provides insights into MyoB IQ motif recognition. The Journal of biological chemistry 4 24790102
2024 Deficiency in Prader-Willi syndrome gene necdin leads to attenuated cardiac contractility. iScience 3 38832028
2022 Identification and genetic analysis of rare variants in myosin family genes in 412 Han Chinese congenital heart disease patients. Molecular genetics & genomic medicine 3 35993536
2025 Analysis of the transcriptional mechanisms of yellowfin tuna (Thunnus albacares) juveniles in response to acute cold stress in brain and muscle tissues. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 1 41412545
2024 Whole Genome Linkage and Association Analyses Identify DLG Associated Protein-1 as a Novel Positional and Biological Candidate Gene for Muscle Strength: The Long Life Family Study. The journals of gerontology. Series A, Biological sciences and medical sciences 1 38808484
2022 Analysis of Plasmodium falciparum myosin B ATPase activity and structure in complex with the calmodulin-like domain of its light chain MLC-B. The Journal of biological chemistry 1 36273584
2025 Influence of Myosin Regulatory Light Chain and Myosin Light Chain Kinase on the Physiological Function of Inner Ear Hair Cells. Journal of the Association for Research in Otolaryngology : JARO 0 40240732

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