MYO18B

MYO18B is an unconventional class XVIII myosin expressed predominantly in striated muscle, where it is essential for the assembly and integrity of the sarcomere (PMID:18761673, PMID:28104788). It localizes to Z-lines of myofibrils rather than the A-bands occupied by conventional myosins, and its targeting to F-actin in myocytes depends on its N-terminal unique domain rather than the motor domain or coiled-coil tail (PMID:18761673). Functionally, MYO18B coordinates the integration of preformed thick and thin filaments into ordered sarcomeres: in its complete absence sarcomeres fail to assemble despite the presence of scattered actin and myosin filaments, and partial loss yields misaligned filaments (PMID:28104788, PMID:27879346). Loss of MYO18B is embryonic lethal in mice with disrupted cardiac myofibrils (PMID:18761673), and in humans truncating mutations cause nemaline myopathy with cardiomyopathy and a Klippel-Feil/myopathy syndrome with abnormal myosin filaments (PMID:27858739, PMID:25748484). Its muscle expression is driven transcriptionally by MEF2 binding to its promoter during myogenic differentiation (PMID:18761673), while protein levels are controlled by polyubiquitination and proteasomal degradation through interaction of its C-terminal tail with the 19S subunit Sug1 (PMID:16499872). Beyond muscle, MYO18B acts as an actin crosslinker required for focal adhesion maturation, which enables PIEZO1-dependent lysosomal exocytosis (PMID:39751400), and its re-expression suppresses anchorage-independent growth across multiple cancer cell types, an activity enhanced by its binding partner HOMER2 (PMID:12209013, PMID:17386922).

1. 2002 Medium

   Whether MYO18B had a cell-autonomous role in malignancy was unknown; restoring its expression directly tested a tumor-suppressive function.

   Evidence Re-expression in lung carcinoma cells with anchorage-independent growth assay

   PMID:12209013

   Open questions at the time

   • Molecular basis of growth suppression not defined
   • No link to a specific signaling pathway in this study
2. 2003 Medium

   Establishing where the protein resides addressed which cellular compartment its function operates in, revealing both nuclear and partial sarcomeric distributions.

   Evidence Immunofluorescence in myoblasts, myotubes, cardiomyocytes, and adult muscle sections

   PMID:12547197

   Open questions at the time

   • Functional consequence of nuclear accumulation not established
   • Sarcomeric sub-localization not mapped to a band
3. 2004 Medium

   The mechanism of MYO18B silencing in cancer was unknown; promoter chromatin analysis showed epigenetic repression underlies its loss.

   Evidence ChIP for H3/H4 acetylation at the MYO18B promoter and TSA-mediated expression rescue in lung cancer lines

   PMID:15101048

   Open questions at the time

   • Does not identify the responsible HDAC or recruiting factor
   • Relationship to promoter methylation not addressed
4. 2005 Medium

   Whether the tumor-suppressive activity generalized beyond lung cancer was tested by re-expression in colorectal lines, refining the phenotype to anchorage-independent proliferation specifically.

   Evidence Re-expression in HT29 and DLD-1 with anchorage-independent versus in vitro growth assays

   PMID:15751041

   Open questions at the time

   • Effector mechanism of anchorage-dependent suppression unknown
5. 2006 High

   How MYO18B protein levels are controlled was unresolved; identifying Sug1 binding established proteasomal turnover as the regulatory mechanism.

   Evidence Yeast two-hybrid, GST pull-down, Co-IP, in vivo polyubiquitination, proteasome inhibition, and Sug1 siRNA rescue

   PMID:16499872

   Open questions at the time

   • E3 ligase responsible for ubiquitination not identified
   • Physiological trigger for degradation unknown
6. 2006 Medium

   The in vivo relevance of growth suppression was tested in mesothelioma, extending the phenotype to motility and tumor formation in animals.

   Evidence MYO18B transfection in EHMES-10 cells with motility assays and SCID mouse xenografts

   PMID:17294804

   Open questions at the time

   • Mechanism of apoptosis induction not defined
   • No molecular partner implicated in this context
7. 2007 Medium

   To find effectors of the suppressive activity, an interaction screen identified HOMER2 and placed MYO18B at F-actin structures where the partner enhances its function.

   Evidence Yeast two-hybrid screen, co-localization at protrusions/stress fibers, co-expression growth assay

   PMID:17386922

   Open questions at the time

   • Structural basis of the HOMER2 interaction unknown
   • How HOMER2 potentiates suppression mechanistically unclear
8. 2008 High

   The physiological function and localization determinants in muscle were unresolved; combined localization, domain mutagenesis, promoter, and knockout work established a Z-line role driven by MEF2 and an N-terminal targeting domain.

   Evidence Immunofluorescence, domain deletion analysis, MEF2 promoter binding, and embryonic-lethal knockout mouse with cardiac histology

   PMID:18761673

   Open questions at the time

   • Direct binding partners at the Z-line not identified
   • Motor/ATPase activity not characterized
9. 2015 Medium

   Whether MYO18B loss causes human disease was answered by truncating mutations linking it causatively to myopathy and abnormal myosin filaments.

   Evidence Exome/autozygome analysis, Western blot, immunostaining, RT-PCR for NMD, and electron microscopy of patient biopsies

   PMID:25748484 PMID:27858739

   Open questions at the time

   • Single case / two families limit genotype-phenotype breadth
   • Molecular step disrupted in filament assembly not resolved in patient tissue
10. 2017 High

    The precise step in sarcomerogenesis that MYO18B controls was unknown; zebrafish allelic series showed it coordinates integration of preformed thick and thin filaments rather than their initial synthesis.

    Evidence Zebrafish frozen/null and hypomorphic mutants with birefringence, immunofluorescence, and electron microscopy of sarcomeres

    PMID:27879346 PMID:28104788

    Open questions at the time

    • Direct molecular interactions enabling filament alignment not identified
    • Fiber-type specificity (fast-twitch) mechanism unexplained
11. 2018 Low

    A signaling context for MYO18B in cancer was probed, linking knockdown to reduced PI3K/AKT/mTOR phosphorylation in hepatocellular carcinoma.

    Evidence siRNA knockdown with proliferation, migration, invasion assays and pathway Western blots in HepG2

    PMID:30390677

    Open questions at the time

    • No direct binding or epistasis establishing the pathway link
    • Oncogenic direction conflicts with tumor-suppressor findings and is not reconciled
12. 2025 Medium

    A non-muscle molecular role was defined, showing MYO18B acts as an actin crosslinker required for focal adhesion maturation that enables PIEZO1-driven lysosomal exocytosis.

    Evidence Genome-wide knockout screen with focal adhesion, lysosomal exocytosis, and glycoproteomic assays

    PMID:39751400

    Open questions at the time

    • Direct biochemical demonstration of actin crosslinking by MYO18B not shown
    • Relationship between this role and its muscle function unclear

• How a single N-terminally targeted myosin mechanically coordinates filament integration, and whether its muscle, adhesion, and tumor-suppressive activities share a common biochemical activity, remains unresolved.
• Motor/ATPase activity and structural basis of F-actin engagement uncharacterized
• Z-line binding partners that mediate sarcomere assembly unidentified
• Reconciliation of tumor-suppressor versus pro-oncogenic reports lacking