MYH9

Last updated
MYH9
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases MYH9 , BDPLT6, DFNA17, EPSTS, FTNS, MHA, NMHC-II-A, NMMHC-IIA, NMMHCA, myosin, heavy chain 9, non-muscle, myosin heavy chain 9, MATINS
External IDs OMIM: 160775 MGI: 107717 HomoloGene: 129835 GeneCards: MYH9
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_002473

NM_022410

RefSeq (protein)

NP_002464
NP_002464.1

NP_071855

Location (UCSC) Chr 22: 36.28 – 36.39 Mb Chr 15: 77.64 – 77.73 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Myosin-9 also known as myosin, heavy chain 9, non-muscle or non-muscle myosin heavy chain IIa (NMMHC-IIA) is a protein which in humans is encoded by the MYH9 gene. [5] [6]

Contents

Non-muscle myosin IIA (NM IIA) is expressed in most cells and tissues where it participates in a variety of processes requiring contractile force, such as cytokinesis, cell migration, polarization and adhesion, maintenance of cell shape, and signal transduction. Myosin IIs are motor proteins that are part of a superfamily composed of more than 30 classes. [7] [8] [9] Class II myosins include muscle and non-muscle myosins that are organized as hexameric molecules consisting of two heavy chains (230 kDa), two regulatory light chains (20 KDa) controlling the myosin activity, and two essential light chains (17 kDa), which stabilize the heavy chain structure. [10] [11] [12] [13] [14]

Gene and protein structure

MYH9 is a large gene spanning more than 106 kilo base pairs on chromosome 22q12.3. It is composed of 41 exons with the first ATG of the open reading frame localized in exon 2 and the stop codon in exon 41. It encodes non-muscle myosin heavy chain IIA (NMHC IIA), a protein of 1,960 amino acids. Consistent with its wide expression in cells and tissues, the promoter region of MYH9 is typical of housekeeping genes having no TATA box but high GC content, with multiple GC boxes. MYH9 is a well-conserved gene through evolution. The mouse ortholog (Myh9) is localized in a syntenic region on chromosome 15 and has the same genomic organization as that of the human gene. It encodes a protein of the same length, with 97.1% amino acid identity with the human MYH9 protein. [15]

Like all class II myosins, the two NMHC IIAs dimerize producing an asymmetric molecular structure recognizable by two heads and a tail domain: the N-terminal half of each heavy chain generates the head domain, which consists of the globular motor domain and the neck domain, and the C-terminal halves of the two heavy chains together form the tail domain. [16] The motor domain, which is organized into four subdomains (SH3-like motif, the upper and the lower 50kDa subdomains, and the converter region) connected by flexible linkers, [17] interacts with filamentous actin to generate force through magnesium-dependent hydrolysis of ATP. The neck acts as a lever arm that amplifies the movement produced by conformational changes of the motor domain, and is the binding site for the light chains through two IQ motifs. The tail domain is fundamental for both dimerization of the heavy chains and formation of NM IIA functional filaments. Two heavy chains dimerize through the tail domain forming a long alpha-helical coiled-coil rod composed of typical heptad repeats. Dimers self-associate though the coiled-coil rods to form myosin filaments. The tail domain ends at the C-terminus with a 34-residue non-helical tailpiece. [14] [16]

Regulation of NM IIA structure and function

There are three paralogs of non-muscle myosin II (NM II), NM IIA, IIB, and IIC, with each having the heavy chain encoded on a different chromosome. All three paralogs appear to bind the same or very similar light chains and share basic properties as to structure and activation, but all three play distinct roles during vertebrate development and adulthood (for general reviews on NM IIs, see [11] [13] [14] ). All NM IIs have two important features: they are MgATPase enzymes that can hydrolyze ATP thereby converting chemical energy into mechanical movement. In addition, they can form bipolar filaments which can interact with and exert tension on actin filaments. These properties provide the basis for all NM II functions. The path to myosin filament formation, which is shared by NM II and smooth muscle myosin, starts with a folded inactive conformation of the NM II monomer which, upon phosphorylation of the 20 KDa light chain unfolds the molecule to produce a globular head region followed by an extended alpha-helical coiled-coil tail. [18] [19] [20] [21] The tail portion of the molecule can interact with other NM IIA hexamers to form bipolar filaments composed of 14-16 molecules.

Phosphorylation of the 20 KDa light chains on Serine 19 and Threonine 18 by a number of different kinases, but most prominently by Rho-dependent kinase and/or by the calcium-calmodulin-dependent myosin light chain kinase, not only linearizes the folded structure but removes the inhibition imposed on the MgATPase activity due to the folded conformation. In addition to phosphorylation of the 20 KDa light chains, the NMHC IIs can also be phosphorylated, but the sites phosphorylated differ among the paralogs. [10] In most cases phosphorylation of NMHC IIA can act to either dissociate the myosin filaments or to prevent filament formation.

In addition to phosphorylation, NM IIA filament assembly and localization can be modulated by interaction with other proteins including S100A4 and Lethal giant larvae (Lgl1). The former is a calcium binding protein and is also known as metastatin, a well-characterized metastatic factor. S100A4 expression is associated with enhanced cell migration through maintenance of cell polarization and inhibition of cell turning. [22] [23] Similar to heavy chain phosphorylation, in vitro binding of S100A to the carboxy-terminal end of the NM IIA coiled-coil region prevents filament formation and S100A4 binding to previously formed filaments promotes filament disassembly. The tumor suppressor protein Lgl1 also inhibits the ability of NM IIA to assemble into filaments in vitro. [24] [25] In addition, it regulates the cellular localization of NM IIA and contributes to the maturation of focal adhesions. Other proteins that are known to interact with NM IIA include the actin binding protein tropomyosin 4.2 [26] and a novel actin stress fiber associated protein, LIM and calponin-homology domains1 (LIMCH1). [27]

Functions specific to NM IIA

NM IIA plays a major role in early vertebrate development. Ablation of NM IIA in mice results in lethality by embryonic day (E) 6.5 due to abnormalities in the visceral endoderm which is disorganized due to a loss of E-cadherin mediated cell-cell adhesions. [28] Lacking a normal polarized columnar layer of endoderm, the abnormal visceral endoderm of NM IIA knockout embryos fails to support the critical step of gastrulation. However, the development of a normal functioning visceral endoderm does not specifically depend on NM IIA since its function can be restored by genetically replacing the NMHC IIA with cDNA encoding NMHC II B (or NMHC IIC) that is under control of the NMHC IIA promoter. [29] These "replacement" mice have a normal visceral endoderm and continue to proceed through gastrulation and undergo organogenesis. However, they die when they fail to develop a normal placenta. Absence of NM IIA results in a compact and underdeveloped labyrinthine layer in the placenta which lacks fetal blood vessel invasion. Moreover, mutant p.R702C NM IIA mice show similar defects in placental formation [30] and mice specifically ablated for NM IIA in the mouse trophoblast-lineage cells demonstrate placental defects similar to mice in which NMHC IIA is genetically replaced by NMHC IIB. [31] There are significant differences in the relative abundance of the three NM II paralogs in various cells and tissues. However, NM IIA appears to be the predominant paralog in both tissues and cells in humans and mice. Mass spectroscopy analysis of the relative abundance of NMHC IIs in mouse tissues and human cell lines [32] shows that NM IIA is predominant, although tissues like the heart vary from cell to cell; myocardial cells contain only NM IIB but NM IIA is more abundant in the non-myocyte cells. NM IIB is predominant in most parts of the brain and spinal cord but NM IIA is relatively more abundant in most other organs and cells lines. Both NM IIA and IIB are expressed early in development with NM IIC expression starting at E 11.5 in mice. Not only do most cells contain more than one paralog but there is evidence that the paralogs can co-assemble intracellularly into heterotypic filaments in a variety of settings in cultured cells. [33] [34] [35]

Clinical significance

MYH9-related disease. Mutations in MYH9 cause a Mendelian autosomal-dominant disorder known as MYH9-related disease (MYH9-RD). [36] [37] [38] [39] All affected individuals present congenital hematological alterations consisting in thrombocytopenia, platelet macrocytosis, and inclusions of the MYH9 protein in the cytoplasm of granulocytes. Most patients develop one or more non-congenital manifestations, including sensorineural deafness, kidney damage, presenile cataracts, and/or elevation of liver enzymes. [39] [40] [41] The term MYH9-RD encompasses four syndromic pictures that were considered for many years as distinct disorders, namely May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome. After the identification of MYH9 as the gene responsible for all of these entities, it was recognized that they actually represent different clinical presentations of the same disease, now known as MYH9-RD or MYH9 disorder. [38] MYH9-RD is a rare disease: prevalence is estimated around 3:1,000,000. The actual prevalence is expected to be higher, as mild forms are often discovered incidentally and patients are frequently misdiagnosed with other disorders. The disease has been reported worldwide and there is no evidence of variation in prevalence across ethnic populations. [42]

Thrombocytopenia can result in a variable degree of bleeding tendency. The majority of patients have no spontaneous bleeding or only mild cutaneous bleeding (easy bruising) and are at risk of significant hemorrhages only after surgery or other invasive procedures, deliveries, or trauma. Some patients have spontaneous mucosal bleeding, such as menorrhagia, epistaxis, and gum bleeding. [39] [40] Severe and life-threatening hemorrhages are not frequent. Platelets of MYH9-RD patients are characterized by a very large size: platelets larger than red blood cells (called "giant platelets") are always present at the examination of peripheral blood smears. [38] [43] Granulocyte inclusions of the NMHC IIA may be evident at the analysis of blood films after conventional staining as cytoplasmic basophilic (light blue) inclusions, called "Döhle-like bodies". [38] [39] More than 50% of MYH9-RD patients develop sensorineural hearing loss. [40] Severity of the hearing impairment is greatly variable, as it ranges from a mild hearing defect that occurs in mid or advanced age to a progressive hearing loss that is evident in the first years of life and rapidly evolves to severe deafness. [44] Kidney damage occurs in about 25% of patients. It presents with proteinuria and often progresses to kidney failure, which, in its most severe forms, may require dialysis and/or kidney transplantation. [40] Around 20% of patients develop presenile cataracts. About 50% of MYH9-RD patients present chronic or intermittent elevation of liver transaminases or gamma-glutamyl transferases: this alteration appears to be benign, as no patients showed evolution to liver dysfunction. [41]

Diagnosis of MYH9-RD is confirmed by the identification of the NMHC IIA inclusions in granulocytes through an immunofluorescence assay on peripheral blood smears and/or by the detection of the causative mutation through mutational screening of the MYH9 gene. [45] [46] [47] [48]

In most cases, MYH9-RD is caused by missense mutations affecting the head or tail domain of the NMHC IIA. Nonsense or frameshift alterations resulting in the deletion of a C-terminal fragment of the NMHC IIA (17 to 40 residues) are involved in approximately 20% of families. In-frame deletions or duplications have been identified in a few cases. [40] [45] [49] The disease is transmitted as an autosomal-dominant trait, however, about 35% of index cases are sporadic. [46] Sporadic forms mainly derive from de novo mutations; rare cases have been explained by germinal or somatic mosaicism. [50] [51] [52]

The incidence and the severity of the non-congenital manifestations of MYH9-RD correlate with the specific MYH9 mutation. The recent definition of genotype-phenotype correlations allows prediction of the clinical evolution of the disease in most cases. [40] [53] Genotype-phenotype correlations have been reported also for the severity of thrombocytopenia, platelet size, and the features of leukocyte inclusions. [40] [43] [54]

Within a phase 2 trial, eltrombopag, an agonist of the thrombopoietin receptor, significantly increased platelet count in 11 out of 12 patients affected with MYH9-RD. [55] ACE-inhibitors or angiotensin II receptor blockers may be effective in reducing proteinuria when given at the early stage of kidney involvement. [56] [57] Cochlear implantation is effective in restoring hearing function in MYH9-RD patients with severe/profound deafness. [58]

Role of MYH9 variants in other human diseases. Evidence obtained in animals indicates that MYH9 acts as a tumor suppressor gene. Silencing of Myh9 in the epithelial cells in mice was associated with the development of squamous cell carcinoma (SCC) of the skin and the head and neck. [59] In another mouse model, ablation of Myh9 in the tongue epithelium led to the development of tongue SCC. [60] In mice predisposed to invasive lobular breast carcinoma (ILBC) because of E-cadherin ablation, the inactivation of Myh9 led to the development of tumors recapitulating the features of human ILBC. [61] Some observations suggest that defective MYH9 expression is associated with oncogenesis and/or tumor progression in human SCC and ILBC, thus also supporting a role for MYH9 as a tumor suppressor in humans. [59] [61]

Genetic variations in MYH9 may be involved in predisposition to chronic kidney disease (CKD). A haplotype of MYH9 (haplotype E1) was previously associated with the increased prevalence of glomerulosclerosis [62] and non-diabetic end stage renal disease [63] in African Americans and in Hispanic Americans. [64] However, subsequent studies showed that this association is explained by strong linkage disequilibrium with two haplotypes (haplotypes G1 and G2) in the neighboring APOL1 gene. [65] [66] [67] Nevertheless, some studies suggest an association of single-nucleotide polymorphisms in MYH9 with CKD that appears to be independent of the linkage with APOL1 G1 and G2. [68] [69] [70]

Inherited MYH9 mutations may be responsible for non-syndromic hearing loss. [71] [72] [73]

Other interactions

MYH9 has been shown to interact with PRKCE. [74]

See also

Notes

Related Research Articles

<span class="mw-page-title-main">Actin</span> Family of proteins

Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over 100 μM; its mass is roughly 42 kDa, with a diameter of 4 to 7 nm.

<span class="mw-page-title-main">Myosin</span> Superfamily of motor proteins

Myosins are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility.

<span class="mw-page-title-main">Intermediate filament</span> Cytoskeletal structure

Intermediate filaments (IFs) are cytoskeletal structural components found in the cells of vertebrates, and many invertebrates. Homologues of the IF protein have been noted in an invertebrate, the cephalochordate Branchiostoma.

<span class="mw-page-title-main">Titin</span> Largest-known protein in human muscles

Titin is a protein that in humans is encoded by the TTN gene. Titin is a protein, over 1 µm in length, that functions as a molecular spring that is responsible for the passive elasticity of muscle. It comprises 244 individually folded protein domains connected by unstructured peptide sequences. These domains unfold when the protein is stretched and refold when the tension is removed.

<span class="mw-page-title-main">Tropomyosin</span> Protein

Tropomyosin is a two-stranded alpha-helical, coiled coil protein found in many animal and fungal cells. In animals, it is an important component of the muscular system which works in conjunction with troponin to regulate muscle contraction. It is present in smooth and striated muscle tissues, which can be found in various organs and body systems, including the heart, blood vessels, respiratory system, and digestive system. In fungi, tropomyosin is found in cell walls and helps maintain the structural integrity of cells.

<span class="mw-page-title-main">MYH7</span> Protein-coding gene in the species Homo sapiens

MYH7 is a gene encoding a myosin heavy chain beta (MHC-β) isoform expressed primarily in the heart, but also in skeletal muscles. This isoform is distinct from the fast isoform of cardiac myosin heavy chain, MYH6, referred to as MHC-α. MHC-β is the major protein comprising the thick filament that forms the sarcomeres in cardiac muscle and plays a major role in cardiac muscle contraction.

<span class="mw-page-title-main">Myofilament</span> The two protein filaments of myofibrils in muscle cells

Myofilaments are the three protein filaments of myofibrils in muscle cells. The main proteins involved are myosin, actin, and titin. Myosin and actin are the contractile proteins and titin is an elastic protein. The myofilaments act together in muscle contraction, and in order of size are a thick one of mostly myosin, a thin one of mostly actin, and a very thin one of mostly titin.

<span class="mw-page-title-main">Telokin</span> Protein domain

Telokin is an abundant protein found in smooth-muscle. It is identical to the C-terminus of myosin light-chain kinase. Telokin may play a role in the stabilization of unphosphorylated smooth-muscle myosin filaments. Because of its origin as the C-terminal end of smooth muscle myosin light chain kinase, it is called "telokin".

<span class="mw-page-title-main">MYL9</span> Protein-coding gene in the species Homo sapiens

Myosin regulatory light polypeptide 9 is a protein that in humans is encoded by the MYL9 gene.

<span class="mw-page-title-main">May–Hegglin anomaly</span> Medical condition

May–Hegglin anomaly (MHA), is a rare genetic disorder of the blood platelets that causes them to be abnormally large.

<span class="mw-page-title-main">TPM1</span> Protein-coding gene in the species Homo sapiens

Tropomyosin alpha-1 chain is a protein that in humans is encoded by the TPM1 gene. This gene is a member of the tropomyosin (Tm) family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells.

<span class="mw-page-title-main">MYH10</span> Protein-coding gene in the species Homo sapiens

Myosin-10 also known as myosin heavy chain 10 or non-muscle myosin IIB (NM-IIB) is a protein that in humans is encoded by the MYH10 gene. Non-muscle myosins are expressed in a wide variety of tissues, but NM-IIB is the only non-muscle myosin II isoform expressed in cardiac muscle, where it localizes to adherens junctions within intercalated discs. NM-IIB is essential for normal development of cardiac muscle and for integrity of intercalated discs. Mutations in MYH10 have been identified in patients with left atrial enlargement.

<span class="mw-page-title-main">Myosin-11</span> Protein-coding gene in the species Homo sapiens

Myosin-11 is a protein that in humans is encoded by the MYH11 gene.

<span class="mw-page-title-main">MYH6</span> Protein-coding gene in the species Homo sapiens

Myosin heavy chain, α isoform (MHC-α) is a protein that in humans is encoded by the MYH6 gene. This isoform is distinct from the ventricular/slow myosin heavy chain isoform, MYH7, referred to as MHC-β. MHC-α isoform is expressed predominantly in human cardiac atria, exhibiting only minor expression in human cardiac ventricles. It is the major protein comprising the cardiac muscle thick filament, and functions in cardiac muscle contraction. Mutations in MYH6 have been associated with late-onset hypertrophic cardiomyopathy, atrial septal defects and sick sinus syndrome.

<span class="mw-page-title-main">Myosin-2</span> Protein-coding gene in the species Homo sapiens

Myosin-2 is a protein that in humans is encoded by the MYH2 gene.

<span class="mw-page-title-main">MYH14</span> Protein-coding gene in the species Homo sapiens

Myosin-14 is a protein that in humans is encoded by the MYH14 gene.

<span class="mw-page-title-main">MYL6</span> Protein-coding gene in the species Homo sapiens

Myosin light polypeptide 6 is a protein that in humans is encoded by the MYL6 gene.

<span class="mw-page-title-main">MYLK</span> Gene of the immunoglobulin superfamily

Myosin light chain kinase, smooth muscle also known as kinase-related protein (KRP) or telokin is an enzyme that in humans is encoded by the MYLK gene.

<span class="mw-page-title-main">MYL6B</span> Protein-coding gene in the species Homo sapiens

Myosin light chain 6B is a protein that in humans is encoded by the MYL6B gene. Myosin is a hexameric ATPase cellular motor protein. It is composed of two heavy chains, two nonphosphorylatable alkali light chains, and two phosphorylatable regulatory light chains. This gene encodes a myosin alkali light chain expressed in both slow-twitch skeletal muscle and in nonmuscle tissue.

<span class="mw-page-title-main">MYH4</span> Protein-coding gene in the species Homo sapiens

Myosin-4 also known as myosin, heavy chain 4 is a protein which in humans is encoded by the MYH4 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000100345 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022443 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Simons M, Wang M, McBride OW, Kawamoto S, Yamakawa K, Gdula D, et al. (August 1991). "Human nonmuscle myosin heavy chains are encoded by two genes located on different chromosomes". Circulation Research. 69 (2): 530–9. doi: 10.1161/01.res.69.2.530 . PMID   1860190.
  6. Lalwani AK, Goldstein JA, Kelley MJ, Luxford W, Castelein CM, Mhatre AN (November 2000). "Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9". American Journal of Human Genetics. 67 (5): 1121–8. doi:10.1016/S0002-9297(07)62942-5. PMC   1288554 . PMID   11023810.
  7. Foth BJ, Goedecke MC, Soldati D (March 2006). "New insights into myosin evolution and classification". Proceedings of the National Academy of Sciences of the United States of America. 103 (10): 3681–6. doi: 10.1073/pnas.0506307103 . PMC   1533776 . PMID   16505385.
  8. Odronitz F, Kollmar M (2007). "Drawing the tree of eukaryotic life based on the analysis of 2,269 manually annotated myosins from 328 species". Genome Biology. 8 (9): R196. doi: 10.1186/gb-2007-8-9-r196 . PMC   2375034 . PMID   17877792.
  9. Sebé-Pedrós A, Grau-Bové X, Richards TA, Ruiz-Trillo I (February 2014). "Evolution and classification of myosins, a paneukaryotic whole-genome approach". Genome Biology and Evolution. 6 (2): 290–305. doi:10.1093/gbe/evu013. PMC   3942036 . PMID   24443438.
  10. 1 2 Dulyaninova NG, Bresnick AR (July 2013). "The heavy chain has its day: regulation of myosin-II assembly". Bioarchitecture. 3 (4): 77–85. doi:10.4161/bioa.26133. PMC   4201608 . PMID   24002531.
  11. 1 2 Heissler SM, Manstein DJ (January 2013). "Nonmuscle myosin-2: mix and match". Cellular and Molecular Life Sciences. 70 (1): 1–21. doi:10.1007/s00018-012-1002-9. PMC   3535348 . PMID   22565821.
  12. Heissler SM, Sellers JR (August 2016). "Kinetic Adaptations of Myosins for Their Diverse Cellular Functions". Traffic. 17 (8): 839–59. doi:10.1111/tra.12388. PMC   5067728 . PMID   26929436.
  13. 1 2 Ma X, Adelstein RS (2014). "The role of vertebrate nonmuscle Myosin II in development and human disease". Bioarchitecture. 4 (3): 88–102. doi:10.4161/bioa.29766. PMC   4201603 . PMID   25098841.
  14. 1 2 3 Vicente-Manzanares M, Ma X, Adelstein RS, Horwitz AR (November 2009). "Non-muscle myosin II takes centre stage in cell adhesion and migration". Nature Reviews. Molecular Cell Biology. 10 (11): 778–90. doi:10.1038/nrm2786. PMC   2834236 . PMID   19851336.
  15. D'Apolito M, Guarnieri V, Boncristiano M, Zelante L, Savoia A (March 2002). "Cloning of the murine non-muscle myosin heavy chain IIA gene ortholog of human MYH9 responsible for May-Hegglin, Sebastian, Fechtner, and Epstein syndromes". Gene. 286 (2): 215–22. doi:10.1016/S0378-1119(02)00455-9. PMID   11943476.
  16. 1 2 Eddinger TJ, Meer DP (August 2007). "Myosin II isoforms in smooth muscle: heterogeneity and function". American Journal of Physiology. Cell Physiology. 293 (2): C493–508. doi:10.1152/ajpcell.00131.2007. PMID   17475667. S2CID   9024520.
  17. Sellers JR (March 2000). "Myosins: a diverse superfamily". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1496 (1): 3–22. doi: 10.1016/S0167-4889(00)00005-7 . PMID   10722873.
  18. Burgess SA, Yu S, Walker ML, Hawkins RJ, Chalovich JM, Knight PJ (October 2007). "Structures of smooth muscle myosin and heavy meromyosin in the folded, shutdown state" (PDF). Journal of Molecular Biology. 372 (5): 1165–78. doi:10.1016/j.jmb.2007.07.014. PMID   17707861.
  19. Jung HS, Komatsu S, Ikebe M, Craig R (August 2008). "Head-head and head-tail interaction: a general mechanism for switching off myosin II activity in cells". Molecular Biology of the Cell. 19 (8): 3234–42. doi:10.1091/mbc.E08-02-0206. PMC   2488288 . PMID   18495867.
  20. Wendt T, Taylor D, Messier T, Trybus KM, Taylor KA (December 1999). "Visualization of head-head interactions in the inhibited state of smooth muscle myosin". The Journal of Cell Biology. 147 (7): 1385–90. doi:10.1083/jcb.147.7.1385. PMC   2174251 . PMID   10613897.
  21. Milton DL, Schneck AN, Ziech DA, Ba M, Facemyer KC, Halayko AJ, et al. (January 2011). "Direct evidence for functional smooth muscle myosin II in the 10S self-inhibited monomeric conformation in airway smooth muscle cells". Proceedings of the National Academy of Sciences of the United States of America. 108 (4): 1421–6. Bibcode:2011PNAS..108.1421M. doi: 10.1073/pnas.1011784108 . PMC   3029703 . PMID   21205888.
  22. Grum-Schwensen B, Klingelhofer J, Berg CH, El-Naaman C, Grigorian M, Lukanidin E, et al. (May 2005). "Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene". Cancer Research. 65 (9): 3772–80. doi: 10.1158/0008-5472.CAN-04-4510 . PMID   15867373.
  23. Li ZH, Bresnick AR (May 2006). "The S100A4 metastasis factor regulates cellular motility via a direct interaction with myosin-IIA". Cancer Research. 66 (10): 5173–80. doi:10.1158/0008-5472.CAN-05-3087. PMID   16707441.
  24. Dahan I, Petrov D, Cohen-Kfir E, Ravid S (January 2014). "The tumor suppressor Lgl1 forms discrete complexes with NMII-A and Par6α-aPKCζ that are affected by Lgl1 phosphorylation". Journal of Cell Science. 127 (Pt 2): 295–304. doi: 10.1242/jcs.127357 . PMID   24213535.
  25. Ravid S (2014). "The tumor suppressor Lgl1 regulates front-rear polarity of migrating cells". Cell Adhesion & Migration. 8 (4): 378–83. doi:10.4161/cam.29387. PMC   4594313 . PMID   25482644.
  26. Hundt N, Steffen W, Pathan-Chhatbar S, Taft MH, Manstein DJ (February 2016). "Load-dependent modulation of non-muscle myosin-2A function by tropomyosin 4.2". Scientific Reports. 6: 20554. Bibcode:2016NatSR...620554H. doi:10.1038/srep20554. PMC   4742800 . PMID   26847712.
  27. Lin YH, Zhen YY, Chien KY, Lee IC, Lin WC, Chen MY, et al. (April 2017). "LIMCH1 regulates nonmuscle myosin-II activity and suppresses cell migration". Molecular Biology of the Cell. 28 (8): 1054–1065. doi:10.1091/mbc.E15-04-0218. PMC   5391182 . PMID   28228547.
  28. Conti MA, Even-Ram S, Liu C, Yamada KM, Adelstein RS (October 2004). "Defects in cell adhesion and the visceral endoderm following ablation of nonmuscle myosin heavy chain II-A in mice". The Journal of Biological Chemistry. 279 (40): 41263–6. doi: 10.1074/jbc.C400352200 . PMID   15292239.
  29. Wang A, Ma X, Conti MA, Liu C, Kawamoto S, Adelstein RS (August 2010). "Nonmuscle myosin II isoform and domain specificity during early mouse development". Proceedings of the National Academy of Sciences of the United States of America. 107 (33): 14645–50. Bibcode:2010PNAS..10714645W. doi: 10.1073/pnas.1004023107 . PMC   2930417 . PMID   20679233.
  30. Zhang Y, Conti MA, Malide D, Dong F, Wang A, Shmist YA, et al. (January 2012). "Mouse models of MYH9-related disease: mutations in nonmuscle myosin II-A". Blood. 119 (1): 238–50. doi:10.1182/blood-2011-06-358853. PMC   3251230 . PMID   21908426.
  31. Crish J, Conti MA, Sakai T, Adelstein RS, Egelhoff TT (October 2013). "Keratin 5-Cre-driven excision of nonmuscle myosin IIA in early embryo trophectoderm leads to placenta defects and embryonic lethality". Developmental Biology. 382 (1): 136–48. doi:10.1016/j.ydbio.2013.07.017. PMC   4186751 . PMID   23911870.
  32. Ma X, Jana SS, Conti MA, Kawamoto S, Claycomb WC, Adelstein RS (November 2010). "Ablation of nonmuscle myosin II-B and II-C reveals a role for nonmuscle myosin II in cardiac myocyte karyokinesis". Molecular Biology of the Cell. 21 (22): 3952–62. doi:10.1091/mbc.E10-04-0293. PMC   2982113 . PMID   20861308.
  33. Beach JR, Hammer JA (May 2015). "Myosin II isoform co-assembly and differential regulation in mammalian systems". Experimental Cell Research. 334 (1): 2–9. doi:10.1016/j.yexcr.2015.01.012. PMC   4433797 . PMID   25655283.
  34. Beach JR, Shao L, Remmert K, Li D, Betzig E, Hammer JA (May 2014). "Nonmuscle myosin II isoforms coassemble in living cells". Current Biology. 24 (10): 1160–6. Bibcode:2014CBio...24.1160B. doi:10.1016/j.cub.2014.03.071. PMC   4108432 . PMID   24814144.
  35. Shutova MS, Asokan SB, Talwar S, Assoian RK, Bear JE, Svitkina TM (September 2017). "Self-sorting of nonmuscle myosins IIA and IIB polarizes the cytoskeleton and modulates cell motility". The Journal of Cell Biology. 216 (9): 2877–2889. doi:10.1083/jcb.201705167. PMC   5584186 . PMID   28701425.
  36. Kelley MJ, Jawien W, Ortel TL, Korczak JF (September 2000). "Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly". Nature Genetics. 26 (1): 106–8. doi:10.1038/79069. PMID   10973260. S2CID   47565254.
  37. Seri M, Cusano R, Gangarossa S, Caridi G, Bordo D, Lo Nigro C, et al. (September 2000). "Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium". Nature Genetics. 26 (1): 103–5. doi:10.1038/79063. PMID   10973259. S2CID   34477122.
  38. 1 2 3 4 Seri M, Pecci A, Di Bari F, Cusano R, Savino M, Panza E, et al. (May 2003). "MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness". Medicine. 82 (3): 203–15. doi: 10.1097/01.md.0000076006.64510.5c . PMID   12792306. S2CID   25549125.
  39. 1 2 3 4 Balduini CL, Pecci A, Savoia A (July 2011). "Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias". British Journal of Haematology. 154 (2): 161–74. doi: 10.1111/j.1365-2141.2011.08716.x . PMID   21542825.
  40. 1 2 3 4 5 6 7 Pecci A, Klersy C, Gresele P, Lee KJ, De Rocco D, Bozzi V, et al. (February 2014). "MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations". Human Mutation. 35 (2): 236–47. doi:10.1002/humu.22476. PMC   6233870 . PMID   24186861.
  41. 1 2 Pecci A, Biino G, Fierro T, Bozzi V, Mezzasoma A, Noris P, et al. (2012). "Alteration of liver enzymes is a feature of the MYH9-related disease syndrome". PLOS ONE. 7 (4): e35986. Bibcode:2012PLoSO...735986P. doi: 10.1371/journal.pone.0035986 . PMC   3338476 . PMID   22558294.
  42. Savoia A, Pecci A (1993). "MYH9-Related Disease". In Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). GeneReviews®. Seattle (WA): University of Washington, Seattle. PMID   20301740.
  43. 1 2 Noris P, Biino G, Pecci A, Civaschi E, Savoia A, Seri M, et al. (August 2014). "Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders". Blood. 124 (6): e4–e10. doi:10.1182/blood-2014-03-564328. PMC   4126341 . PMID   24990887.
  44. Verver EJ, Topsakal V, Kunst HP, Huygen PL, Heller PG, Pujol-Moix N, et al. (January 2016). "Nonmuscle Myosin Heavy Chain IIA Mutation Predicts Severity and Progression of Sensorineural Hearing Loss in Patients With MYH9-Related Disease". Ear and Hearing. 37 (1): 112–20. doi:10.1097/AUD.0000000000000198. PMID   26226608. S2CID   27310678.
  45. 1 2 Kunishima S, Matsushita T, Kojima T, Sako M, Kimura F, Jo EK, et al. (January 2003). "Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations". Laboratory Investigation; A Journal of Technical Methods and Pathology. 83 (1): 115–22. doi: 10.1097/01.LAB.0000050960.48774.17 . PMID   12533692.
  46. 1 2 Savoia A, De Rocco D, Panza E, Bozzi V, Scandellari R, Loffredo G, et al. (April 2010). "Heavy chain myosin 9-related disease (MYH9 -RD): neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder". Thrombosis and Haemostasis. 103 (4): 826–32. doi:10.1160/TH09-08-0593. hdl: 11336/15532 . PMID   20174760. S2CID   3819344.
  47. Kitamura K, Yoshida K, Shiraishi Y, Chiba K, Tanaka H, Furukawa K, et al. (November 2013). "Normal neutrophil myosin IIA localization in an immunofluorescence analysis can rule out MYH9 disorders". Journal of Thrombosis and Haemostasis. 11 (11): 2071–3. doi:10.1111/jth.12406. PMID   24106837. S2CID   32839438.
  48. Greinacher A, Pecci A, Kunishima S, Althaus K, Nurden P, Balduini CL, et al. (July 2017). "Diagnosis of inherited platelet disorders on a blood smear: a tool to facilitate worldwide diagnosis of platelet disorders". Journal of Thrombosis and Haemostasis. 15 (7): 1511–1521. doi: 10.1111/jth.13729 . PMID   28457011.
  49. Saposnik B, Binard S, Fenneteau O, Nurden A, Nurden P, Hurtaud-Roux MF, et al. (July 2014). "Mutation spectrum and genotype-phenotype correlations in a large French cohort of MYH9-Related Disorders". Molecular Genetics & Genomic Medicine. 2 (4): 297–312. doi:10.1002/mgg3.68. PMC   4113270 . PMID   25077172.
  50. Kunishima S, Matsushita T, Yoshihara T, Nakase Y, Yokoi K, Hamaguchi M, et al. (February 2005). "First description of somatic mosaicism in MYH9 disorders". British Journal of Haematology. 128 (3): 360–5. doi: 10.1111/j.1365-2141.2004.05323.x . PMID   15667538. S2CID   36240023.
  51. Kunishima S, Takaki K, Ito Y, Saito H (April 2009). "Germinal mosaicism in MYH9 disorders: a family with two affected siblings of normal parents". British Journal of Haematology. 145 (2): 260–2. doi:10.1111/j.1365-2141.2009.07584.x. PMID   19208103. S2CID   205265342.
  52. Kunishima S, Kitamura K, Matsumoto T, Sekine T, Saito H (June 2014). "Somatic mosaicism in MYH9 disorders: the need to carefully evaluate apparently healthy parents". British Journal of Haematology. 165 (6): 885–7. doi: 10.1111/bjh.12797 . PMID   24611568.
  53. Pecci A, Panza E, Pujol-Moix N, Klersy C, Di Bari F, Bozzi V, et al. (March 2008). "Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease". Human Mutation. 29 (3): 409–17. doi: 10.1002/humu.20661 . hdl: 11336/105263 . PMID   18059020. S2CID   12650830.
  54. Kunishima S, Yoshinari M, Nishio H, Ida K, Miura T, Matsushita T, et al. (March 2007). "Haematological characteristics of MYH9 disorders due to MYH9 R702 mutations". European Journal of Haematology. 78 (3): 220–6. doi:10.1111/j.1600-0609.2006.00806.x. PMID   17241369. S2CID   22638636.
  55. Pecci A, Gresele P, Klersy C, Savoia A, Noris P, Fierro T, et al. (December 2010). "Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations". Blood. 116 (26): 5832–7. doi: 10.1182/blood-2010-08-304725 . PMID   20844233. S2CID   206894973.
  56. Pecci A, Granata A, Fiore CE, Balduini CL (August 2008). "Renin-angiotensin system blockade is effective in reducing proteinuria of patients with progressive nephropathy caused by MYH9 mutations (Fechtner-Epstein syndrome)". Nephrology, Dialysis, Transplantation. 23 (8): 2690–2. doi: 10.1093/ndt/gfn277 . PMID   18503011.
  57. Sekine T, Konno M, Sasaki S, Moritani S, Miura T, Wong WS, et al. (July 2010). "Patients with Epstein-Fechtner syndromes owing to MYH9 R702 mutations develop progressive proteinuric renal disease". Kidney International. 78 (2): 207–14. doi: 10.1038/ki.2010.21 . PMID   20200500.
  58. Pecci A, Verver EJ, Schlegel N, Canzi P, Boccio CM, Platokouki H, et al. (June 2014). "Cochlear implantation is safe and effective in patients with MYH9-related disease". Orphanet Journal of Rare Diseases. 9: 100. doi: 10.1186/1750-1172-9-100 . PMC   4105151 . PMID   24980457.
  59. 1 2 Schramek D, Sendoel A, Segal JP, Beronja S, Heller E, Oristian D, et al. (January 2014). "Direct in vivo RNAi screen unveils myosin IIa as a tumor suppressor of squamous cell carcinomas". Science. 343 (6168): 309–13. Bibcode:2014Sci...343..309S. doi:10.1126/science.1248627. PMC   4159249 . PMID   24436421.
  60. Conti MA, Saleh AD, Brinster LR, Cheng H, Chen Z, Cornelius S, et al. (September 2015). "Conditional deletion of nonmuscle myosin II-A in mouse tongue epithelium results in squamous cell carcinoma". Scientific Reports. 5: 14068. Bibcode:2015NatSR...514068A. doi:10.1038/srep14068. PMC   4572924 . PMID   26369831.
  61. 1 2 Kas SM, de Ruiter JR, Schipper K, Annunziato S, Schut E, Klarenbeek S, et al. (August 2017). "Insertional mutagenesis identifies drivers of a novel oncogenic pathway in invasive lobular breast carcinoma". Nature Genetics. 49 (8): 1219–1230. doi:10.1038/ng.3905. PMID   28650484. S2CID   3255229.
  62. Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, et al. (October 2008). "MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis". Nature Genetics. 40 (10): 1175–84. doi:10.1038/ng.226. PMC   2827354 . PMID   18794856.
  63. Kao WH, Klag MJ, Meoni LA, Reich D, Berthier-Schaad Y, Li M, et al. (October 2008). "MYH9 is associated with nondiabetic end-stage renal disease in African Americans". Nature Genetics. 40 (10): 1185–92. doi:10.1038/ng.232. PMC   2614692 . PMID   18794854.
  64. Behar DM, Rosset S, Tzur S, Selig S, Yudkovsky G, Bercovici S, et al. (May 2010). "African ancestry allelic variation at the MYH9 gene contributes to increased susceptibility to non-diabetic end-stage kidney disease in Hispanic Americans". Human Molecular Genetics. 19 (9): 1816–27. doi:10.1093/hmg/ddq040. PMC   2850615 . PMID   20144966.
  65. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, et al. (August 2010). "Association of trypanolytic ApoL1 variants with kidney disease in African Americans". Science. 329 (5993): 841–5. Bibcode:2010Sci...329..841G. doi:10.1126/science.1193032. PMC   2980843 . PMID   20647424.
  66. Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, et al. (September 2010). "Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene". Human Genetics. 128 (3): 345–50. doi:10.1007/s00439-010-0861-0. PMC   2921485 . PMID   20635188.
  67. Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, et al. (November 2011). "APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy". Journal of the American Society of Nephrology. 22 (11): 2129–37. doi:10.1681/ASN.2011040388. PMC   3231787 . PMID   21997394.
  68. Cooke JN, Bostrom MA, Hicks PJ, Ng MC, Hellwege JN, Comeau ME, et al. (April 2012). "Polymorphisms in MYH9 are associated with diabetic nephropathy in European Americans". Nephrology, Dialysis, Transplantation. 27 (4): 1505–11. doi:10.1093/ndt/gfr522. PMC   3315672 . PMID   21968013.
  69. Cheng W, Zhou X, Zhu L, Shi S, Lv J, Liu L, et al. (August 2011). "Polymorphisms in the nonmuscle myosin heavy chain 9 gene (MYH9) are associated with the progression of IgA nephropathy in Chinese". Nephrology, Dialysis, Transplantation. 26 (8): 2544–9. doi: 10.1093/ndt/gfq768 . PMID   21245129.
  70. O'Seaghdha CM, Parekh RS, Hwang SJ, Li M, Köttgen A, Coresh J, et al. (June 2011). "The MYH9/APOL1 region and chronic kidney disease in European-Americans". Human Molecular Genetics. 20 (12): 2450–6. doi:10.1093/hmg/ddr118. PMC   3098737 . PMID   21429915.
  71. Wu CC, Lin YH, Lu YC, Chen PJ, Yang WS, Hsu CJ, et al. (2013). "Application of massively parallel sequencing to genetic diagnosis in multiplex families with idiopathic sensorineural hearing impairment". PLOS ONE. 8 (2): e57369. Bibcode:2013PLoSO...857369W. doi: 10.1371/journal.pone.0057369 . PMC   3579845 . PMID   23451214.
  72. Kim SJ, Lee S, Park HJ, Kang TH, Sagong B, Baek JI, et al. (October 2016). "Genetic association of MYH genes with hereditary hearing loss in Korea". Gene. 591 (1): 177–82. doi:10.1016/j.gene.2016.07.011. PMID   27393652.
  73. Miyagawa M, Naito T, Nishio SY, Kamatani N, Usami S (2013). "Targeted exon sequencing successfully discovers rare causative genes and clarifies the molecular epidemiology of Japanese deafness patients". PLOS ONE. 8 (8): e71381. Bibcode:2013PLoSO...871381M. doi: 10.1371/journal.pone.0071381 . PMC   3742761 . PMID   23967202.
  74. England K, Ashford D, Kidd D, Rumsby M (June 2002). "PKC epsilon is associated with myosin IIA and actin in fibroblasts". Cellular Signalling. 14 (6): 529–36. doi:10.1016/S0898-6568(01)00277-7. PMID   11897493.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.