Disease relevance of MYO6

• MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice, is mutated in autosomal dominant nonsyndromic hearing loss [1].
• Inhibiting myosin VI expression in high-grade ovarian carcinoma cells impeded cell spreading and migration in vitro [2].
• These results indicate that myosin VI immunoanalog is expressed in protist Amoeba proteus and may be involved in vesicle translocation and cell locomotion [3].
• When optineurin is depleted from cells using RNA interference, myosin VI is lost from the Golgi complex, the Golgi is fragmented and exocytosis of vesicular stomatitis virus G-protein to the plasma membrane is dramatically reduced [4].
• These results support that myosin VI is critical in maintaining the malignant properties of the majority of human prostate cancers diagnosed today [5].

Psychiatry related information on MYO6

• Although myosin-VI can be recruited to clathrin-coated pits, we find no requirement for myosin-VI motor activity in endocytosis in NRK cells [6].

High impact information on MYO6

• Myosin VI can move along actin filaments to serve as a transport motor [7].
• We show that sv encodes an unconventional myosin heavy chain, myosin VI, which is expressed within the sensory hair cells of the inner ear, and appears to be required for maintaining their structural integrity [8].
• The recently solved structure of the myosin VI motor demonstrates that the unique insert at the end of the motor is responsible for the reversal of the normal myosin directionality [9].
• Myosin VI: a structural role in actin organization important for protein and organelle localization and trafficking [10].
• We hypothesize that the main function of myosin VI is to bind tightly to actin, stabilizing actin cytoskeletal structures and linking actin structures to membranes and protein complexes [10].

Biological context of MYO6

• The corresponding human gene, MYO6, is located on chromosome 6q13 [1].
• We describe the mapping of a new deafness locus, DFNA22, on chromosome 6q13 in a family affected by a nonsyndromic dominant form of deafness (NSAD), and the subsequent identification of a missense mutation in the MYO6 gene in all members of the family with hearing loss [1].
• In families with recessively inherited deafness, DFNB37, our sequence analyses of MYO6 reveal a frameshift mutation (36-37insT), a nonsense mutation (R1166X), and a missense mutation (E216V) [11].
• The MYO6 gene maps to human chromosome 6q13 [12].
• Myosin VI, an actin-dependent, minus-end directed mechanoenzyme, has been implicated in clathrin-mediated endocytosis in epithelial cells [13].

Anatomical context of MYO6

• Taken together, these data indicate that myosin VI and Dab2 facilitate CFTR endocytosis by a mechanism that requires actin filaments [13].
• A null mutation in myosin VI in the congenitally deaf Snell's waltzer mice (Myo6(sv)) results in fusion of stereocilia and subsequent progressive loss of hair cells, beginning soon after birth, thus reinforcing the vital role of cytoskeletal proteins in inner ear hair cells [14].
• Myo6 participates in two steps of endocytic trafficking; it is recruited to both clathrin-coated pits and to ensuing uncoated endocytic vesicles (UCV) [15].
• These data suggest that myo6 is an accessory protein required for the efficient transportation of nascent endocytic vesicles from the actin-rich peripheries of epithelial cells, allowing for timely fusion of endocytic vesicles with the early endosome [16].
• Overexpression of GFP-M6tail had no effect on a variety of organelle markers; however, GFP-M6tail displaced the endogenous myo6 from nascent vesicles and resulted in a significant delay in transferrin uptake [16].

Associations of MYO6 with chemical compounds

• However, when coupled to 200-nm polystyrene beads (comparable to intracellular vesicles in size) at a ratio of one head per bead, single-headed myosin-VI moves processively with large (40-nm) steps [17].
• Myosin VI altered at threonine 406 stabilizes actin filaments in vivo [18].

Physical interactions of MYO6

• The present findings suggest that myosin VI plays a role in transporting DOC-2/DAB2, a Ras cascade signaling molecule, thus involved in Ras signaling pathways [19].
• In a yeast 2-hybrid screen we identified optineurin as a binding partner for myosin VI at the Golgi complex and confirmed this interaction in a range of protein interaction studies [4].
• LMTK2 binds to the WWY site in the C-terminal myosin VI tail, the same site as the endocytic adaptor protein Dab2 [20].

Enzymatic interactions of MYO6

• In A431 cells in which cell surface ruffling was stimulated by EGF, myosin VI was phosphorylated and recruited into the newly formed ruffles along with ezrin and myosin V [21].

Regulatory relationships of MYO6

• The goal of this study was to determine whether myosin VI regulates CFTR endocytosis [13].
• Myosin-VI is only recruited to clathrin-coated vesicles in cells that express high levels of Dab2, a clathrin-binding adapter protein [6].
• Nuclear myosin VI enhances RNA polymerase II-dependent transcription [22].

Other interactions of MYO6

• However, the myosin VI tail fragment had no effect on the recycling of endocytosed CFTR or on fluid-phase endocytosis [13].
• The C-terminal domain but not the N-terminal domain of DOC-2/DAB2 functions as a myosin VI anchoring site [19].
• Binding of internalized receptors to the PDZ domain of GIPC/synectin recruits myosin VI to endocytic vesicles [15].
• GIPC, a PDZ-domain containing adapter protein, co-assembles with myosin-VI on these vesicles [6].
• Myosin VI is an unconventional myosin that may play a role in vesicular membrane traffic through actin rich regions of the cytoplasm in eukaryotic cells [21].

Analytical, diagnostic and therapeutic context of MYO6

• In this report, we refined the map position of human myosin VI (MYO6) by radiation hybrid mapping and characterized the genomic structure of myosin VI [23].
• We visualized the myosin VI construct bound to actin using cryo-electron microscopy and image analysis, and found that an ADP-mediated conformational change in the domain distal to the motor, a structure likely to be the effective lever arm, is in the opposite direction to that observed for other myosins [24].
• The affinity purified antibodies were highly specific for myosin VI by immunoblotting and immunoprecipitation and were used to study the localization of the protein by immunofluorescence and immunoelectron microscopy [21].
• We observed, using an optical tweezers force transducer, that monomeric myosin VI is a non-processive motor which, despite a relatively short lever arm, generates a large working stroke of 18 nm [25].
• Northern blot analysis revealed that FMVIA mRNA is broadly expressed and most abundant in kidney, a pattern similar to that previously reported for mammalian myosin VI [26].

References