MYO10

MYO10 (Myosin X) is an unconventional actin-based motor that drives the initiation and elongation of filopodia and related actin-rich membrane protrusions across neuronal, immune, reproductive, and epithelial contexts (PMID:16371656, PMID:28289096, PMID:35470858). Its motor domain is required to target the protein to filopodial tips and to power intrafilopodial motility (PMID:16371656), with the actin-binding interface functioning to reorganize cortical actin filaments at the membrane-cortex interface during filopodium initiation [PMID:bio_10.1101_2025.05.29.656896]; the tail domain, including its coiled-coil dimerization region, is in turn required for movement toward tips and for sustained filopodial elongation (PMID:38043799). Beyond canonical filopodia, MYO10 promotes tunneling nanotube formation through the F2 lobe of its FERM domain (PMID:23886947) and is recruited to PtdIns(3,4,5)P3 via its PH domain to drive axon formation (PMID:22590642). The brain additionally expresses a headless isoform lacking the motor domain that localizes to the plasma membrane but does not induce filopodia, while full-length motorized MYO10 is required for prenatal development including neural tube closure and digit formation (PMID:16371656, PMID:30679680). Through its filopodial activity MYO10 supports N-cadherin-mediated neurogenic migration (PMID:25491426), transzonal projections during folliculogenesis (PMID:35470858), and basement-membrane integrity at pre-invasive tumor boundaries, limiting cancer-cell dispersal (PMID:36283390). MYO10 is an unstable protein degraded via a phosphorylated degron motif by UbcH7 and β-TrCP1; phosphorylated MYO10 transiently accumulates at the centrosome and midbody during mitosis, and its dysregulation increases genomic instability and cGAS/STING-dependent inflammatory signaling (PMID:34524844, PMID:37200188). In colorectal cancer it additionally interacts with RACK1 and activates integrin/Src/FAK signaling to promote progression and metastasis (PMID:35912545).

1. 2006 High

   Established that the MYO10 motor domain is mechanistically necessary for filopodial tip targeting and intrafilopodial motility, and that the brain expresses a distinct headless isoform retaining only the tail modules.

   Evidence Live-cell imaging of GFP-tagged full-length versus headless constructs plus immunoblot/immunofluorescence in CAD neuronal cells and mouse brain

   PMID:16371656

   Open questions at the time

   • Did not define how the motor domain engages cortical actin
   • Functional role of the headless isoform left unresolved
2. 2012 High

   Showed that PH-domain recruitment of MYO10 to PtdIns(3,4,5)P3 drives axon formation, linking phosphoinositide signaling to MYO10-dependent neurite specification independent of motor activity in the gain-of-function setting.

   Evidence RNAi knockdown and EGFP-tagged mutant overexpression in hippocampal neurons with in vivo neocortical migration assay

   PMID:22590642

   Open questions at the time

   • Downstream cargo at the axon tip not identified
   • Relationship to filopodial initiation machinery unclear
3. 2013 High

   Demonstrated that MYO10 promotes tunneling nanotube formation and vesicle transfer, requiring both motor and tail (specifically the FERM F2 lobe) and acting independently of integrin and N-cadherin binding.

   Evidence Domain-deletion/mutation constructs with TNT number and vesicle-transfer quantification in CAD cells

   PMID:23886947

   Open questions at the time

   • F2-lobe binding partner for TNT formation not identified
   • Mechanistic distinction between TNT and filopodia formation unresolved
4. 2014 Medium

   Connected MYO10 filopodial function to neurogenic migration by showing N-cadherin can rescue the migration deficit of MYO10 loss, implicating cell-matrix adhesion and polarity.

   Evidence shRNA knockdown in NLT cells with wound-healing/Golgi-polarity, adhesion, and N-cadherin rescue assays

   PMID:25491426

   Open questions at the time

   • Direct physical link between MYO10 and N-cadherin not established here
   • Limited mechanistic depth, single lab
5. 2017 High

   Placed MYO10 downstream of Cdc42 specifically in filopodia induction, dissociating its role from general cell morphology and phagocytosis.

   Evidence Myo10 knockout mice and live imaging of Lifeact-EGFP macrophages with phagocytosis assays

   PMID:28289096

   Open questions at the time

   • Molecular link between Cdc42 and MYO10 not defined
   • Physiological consequence of macrophage filopodia loss not assessed
6. 2019 High

   Distinguished motorized from headless MYO10 in vivo, showing full-length protein is required for prenatal development and vasculature regression while the headless isoform localizes to membrane without inducing filopodia.

   Evidence Isoform-specific reporter knockout mice with MRI, retinal whole-mounts, and in vitro filopodia assays

   PMID:30679680

   Open questions at the time

   • Mechanism of membrane targeting of headless isoform independent of MyTH4-FERM unexplained
   • Tissue-specific developmental targets not pinpointed
7. 2021 High

   Revealed that MYO10 is an unstable protein controlled by UbcH7/β-TrCP1 ubiquitin-mediated degradation and that its levels gate genomic instability and cGAS/STING inflammatory signaling.

   Evidence Protein stability and ubiquitination assays with overexpression/depletion in cancer cells and mouse tumor models

   PMID:34524844

   Open questions at the time

   • Kinase generating the degron phosphorylation not identified at this stage
   • Mechanistic link from a motor protein to genome stability unclear
8. 2022 Medium

   Extended MYO10 filopodial function to tissue boundaries and adhesion signaling: it maintains basement-membrane integrity limiting tumor dispersal, supports transzonal projections in folliculogenesis, and stabilizes RACK1 to activate integrin/Src/FAK signaling in colorectal cancer.

   Evidence MYO10 depletion in DCIS xenografts and granulosa-oocyte complexes; LC-MS/MS, Co-IP, ubiquitination and metastasis assays in CRC cells

   PMID:35470858 PMID:35912545 PMID:36283390

   Open questions at the time

   • RACK1 interaction rests on a single lab's Co-IP/MS
   • How filopodia mechanically preserve basement membrane not resolved
9. 2023 High

   Defined a phosphorylated degron motif driving β-TrCP1-dependent turnover and showed phosphorylated MYO10 transiently localizes to centrosome then midbody during mitosis, mechanistically linking its degradation control to mitotic fidelity and inflammation.

   Evidence Degron and phosphosite mutagenesis with mitotic localization imaging, depletion phenotypes, and Taxol sensitivity assays

   PMID:37200188

   Open questions at the time

   • Identity of the responsible kinase not established
   • Functional role of MYO10 at centrosome/midbody mechanistically undefined
10. 2025 Medium

    Pinpointed the actin-binding interface as the key element for filopodium initiation, arguing MYO10's primary role is to reorganize cortical actin at the membrane-cortex interface rather than to reduce membrane tension during elongation.

    Evidence Site-directed mutagenesis of the actin-binding interface with quantitative filopodia and intrafilopodial motility imaging across cell lines (preprint)

    PMID:bio_10.1101_2025.05.29.656896

    Open questions at the time

    • Preprint, single lab
    • Direct structural basis of cortical actin reorganization not resolved

• How MYO10's filopodial motor activity is integrated with its mitotic, genome-stability, and inflammatory functions, and what upstream kinase phosphorylates its degron, remain unresolved.
• Kinase generating the degron phosphorylation unknown
• Mechanistic connection between cytoplasmic motor function and centrosome/midbody role undefined
• Direct cargo bound by tail domains in most contexts unidentified