MYO18A

MYO18A is an unconventional myosin that functions primarily as a scaffolding and adaptor protein rather than a force-generating motor, possessing an ATP-insensitive actin-binding site in its N-terminal domain and negligible ATPase activity, while forming stable dimers through its C-terminal coiled-coil domain (PMID:15835906, PMID:38784114). In non-muscle cells, MYO18A scaffolds the PAK2/βPIX/GIT1 complex at lamellipodia to promote Rac1-dependent cell migration and assembles a Smad4–MYO18A–PP1A complex that dephosphorylates PAK1-T423 to suppress β-catenin nuclear signaling (PMID:19923322, PMID:25014165, PMID:34799729). MYO18A also partners with GOLPH3 at the trans-Golgi network to participate in vesicle budding and Golgi dynamics, and its PDZ domain and KE-rich domain direct isoform-specific subcellular targeting to ER-Golgi membranes or actin fibers, respectively (PMID:12761286, PMID:15582604, PMID:40055842). The striated muscle-specific γ-isoform localizes to sarcomeric A-bands and is essential for cardiac sarcomere integrity, as genetic deletion in mice causes embryonic lethality with sarcomere disorganization (PMID:38784114).

1. 2003 Medium

   Establishing that MYO18A exists as distinct isoforms with the PDZ domain dictating ER-Golgi localization resolved how a single gene achieves multiple subcellular distributions.

   Evidence Fluorescence microscopy and subcellular fractionation of PDZ-containing (α) versus PDZ-lacking (β) isoforms in mammalian cells

   PMID:12761286

   Open questions at the time

   • Ligands or binding partners of the PDZ domain were not identified
   • Functional consequence of ER-Golgi targeting was not tested
2. 2005 High

   Demonstrating that MYO18A binds actin through an ATP-insensitive site and dimerizes via coiled-coil domains established it as a scaffolding myosin rather than a conventional motor, while the KE-rich domain was mapped as a distinct actin-association determinant.

   Evidence Cosedimentation with truncated constructs, chemical cross-linking, co-IP of deletion mutants, live-cell imaging in HeLa cells

   PMID:15582604 PMID:15835906

   Open questions at the time

   • Whether MYO18A retains any residual motor activity under specific conditions was not resolved
   • The structural basis for ATP-insensitive actin binding was not determined
3. 2005 Medium

   Identification of MYO18A as a translocation partner generating oncogenic fusion kinases (MYO18A-FGFR1) established its genomic locus as a recurrent breakpoint in myeloproliferative neoplasms.

   Evidence RT-PCR, FISH, and bubble-PCR in patient samples with t(8;17) translocation

   PMID:15800673 PMID:19006078

   Open questions at the time

   • MYO18A's contribution to the fusion beyond its promoter/dimerization domain was not dissected
   • Only single-case evidence for each fusion
4. 2009 High

   Discovery that MYO18A scaffolds the PAK2/βPIX/GIT1 complex at lamellipodia and that its loss causes complex relocalization to focal adhesions with impaired migration answered how an enzymatically inactive myosin promotes cell motility.

   Evidence Proteomic/MS identification, siRNA knockdown with rescue, co-IP, in vitro binding, and migration assays in mammalian cells

   PMID:19923322

   Open questions at the time

   • The precise actin-based transport mechanism was not reconstituted in vitro
   • Whether MYO18A carries cargo processively along actin or acts statically was unknown
5. 2014 High

   Mapping the MYO18Aα–βPIX direct interaction to the extreme C-terminal PAWDETNL motif of βPIX, and showing its disruption reduces Rac1 activity, provided the molecular basis for MYO18A-driven lamellipodial dynamics.

   Evidence Deletion mutagenesis of βPIX, Rac1 activity assay, migration assays

   PMID:25014165

   Open questions at the time

   • The reciprocal binding site on MYO18A was not fully defined
   • In vivo relevance in tissue migration contexts was not tested
6. 2015 Medium

   Showing that MYO18A isoforms (SP-R210L/S) differentially associate with CD14 and SR-A to regulate macrophage LPS responses expanded MYO18A's scaffolding role to innate immune receptor trafficking.

   Evidence Dominant-negative disruption, co-IP, flow cytometry, and macrophage stimulation assays

   PMID:25346337 PMID:25965346

   Open questions at the time

   • The structural determinants distinguishing SP-R210L and SP-R210S receptor interactions were not mapped
   • Relevance to in vivo immune responses was not established
7. 2021 High

   Identification of the Smad4–MYO18A–PP1A ternary complex, where MYO18A scaffolds PP1A via its RVFFR motif to dephosphorylate PAK1-T423 and suppress β-catenin signaling, revealed a second major signaling-scaffold function for MYO18A.

   Evidence LC-MS/MS, co-IP, domain mutagenesis (RVFFR and CC domains), in vitro and in vivo functional experiments

   PMID:34799729

   Open questions at the time

   • Whether this complex operates outside cholangiocarcinoma contexts was not tested
   • Regulation of complex assembly and disassembly is unknown
8. 2023 Medium

   Demonstrating that MYO18A's coiled-coil/C-extension undergoes liquid-liquid phase separation with Tanc1/2 TPR domains introduced a biophysical dimension to MYO18A's scaffolding mechanism.

   Evidence Size exclusion chromatography and LLPS assay in vitro and in cultured cells

   PMID:38092135

   Open questions at the time

   • Physiological relevance of LLPS-mediated condensates in cells was not demonstrated
   • Whether LLPS regulates MYO18A's scaffolding functions was not tested
9. 2024 Medium

   Genetic knockout showing embryonic lethality with cardiac sarcomere disorganization, combined with A-band localization and negligible ATPase activity, established MYO18Aγ as an essential structural component of striated muscle sarcomeres.

   Evidence Mouse Myo18a knockout, localization studies, biochemical ATPase assay

   PMID:38784114

   Open questions at the time

   • The binding partners anchoring MYO18Aγ at A-bands are not identified
   • Whether conditional adult knockout causes cardiomyopathy was not tested
10. 2025 Medium

    Showing that GOLPH3–MYO18A interaction at the TGN is enhanced by golgicide A and drives Golgi dispersion linked to NLRP3-dependent pyroptosis connected MYO18A's Golgi scaffolding to inflammatory cell death.

    Evidence Co-IP, confocal co-localization, caspase-1 activity assay, xenograft model in lung cancer stem cells

    PMID:40055842

    Open questions at the time

    • Whether MYO18A directly participates in normal TGN vesicle budding independent of pharmacological perturbation is not resolved
    • The stoichiometry and regulation of the GOLPH3–MYO18A complex are unknown

• Key unresolved questions include: (1) whether MYO18A possesses any residual mechanochemical activity under physiological conditions; (2) the structural basis for its ATP-insensitive actin binding; (3) how its multiple scaffolding functions (PAK2/βPIX/GIT1, Smad4/PP1A, GOLPH3) are coordinated or segregated across isoforms and tissues.
• No high-resolution structure of MYO18A motor or N-terminal domain
• No reconstituted motility or processivity assay
• Tissue-specific isoform functions are poorly integrated