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Muscle-specific stress fibers give rise to sarcomeres in cardiomyocytes.
Fenix AM, Neininger AC, Taneja N, Hyde K, Visetsouk MR, Garde RJ, Liu B, Nixon BR, Manalo AE, Becker JR, Crawley SW, Bader DM, Tyska MJ, Liu Q, Gutzman JH, Burnette DT
(2018) Elife 7:
MeSH Terms: Actin Cytoskeleton, Actins, Cell Line, Cell Line, Tumor, HeLa Cells, Humans, Microfilament Proteins, Microscopy, Confocal, Molecular Motor Proteins, Muscle Fibers, Skeletal, Myocytes, Cardiac, Myosin Heavy Chains, Nonmuscle Myosin Type IIB, RNA Interference, Sarcomeres, Stress Fibers
Show Abstract · Added March 27, 2019
The sarcomere is the contractile unit within cardiomyocytes driving heart muscle contraction. We sought to test the mechanisms regulating actin and myosin filament assembly during sarcomere formation. Therefore, we developed an assay using human cardiomyocytes to monitor sarcomere assembly. We report a population of muscle stress fibers, similar to actin arcs in non-muscle cells, which are essential sarcomere precursors. We show sarcomeric actin filaments arise directly from muscle stress fibers. This requires formins (e.g., FHOD3), non-muscle myosin IIA and non-muscle myosin IIB. Furthermore, we show short cardiac myosin II filaments grow to form ~1.5 μm long filaments that then 'stitch' together to form the stack of filaments at the core of the sarcomere (i.e., the A-band). A-band assembly is dependent on the proper organization of actin filaments and, as such, is also dependent on FHOD3 and myosin IIB. We use this experimental paradigm to present evidence for a unifying model of sarcomere assembly.
© 2018, Fenix et al.
0 Communities
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16 MeSH Terms
Next-generation sequencing identifies pathogenic and modifier mutations in a consanguineous Chinese family with hypertrophic cardiomyopathy.
Zhang X, Xie J, Zhu S, Chen Y, Wang L, Xu B
(2017) Medicine (Baltimore) 96: e7010
MeSH Terms: Adolescent, Adult, Aged, Asian Continental Ancestry Group, Calcium Channels, L-Type, Cardiac Myosins, Cardiomyopathy, Hypertrophic, Familial, Carrier Proteins, Child, China, Consanguinity, Echocardiography, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotyping Techniques, Humans, Male, Middle Aged, Mutation, Myosin Heavy Chains, Sequence Analysis, Young Adult
Show Abstract · Added September 11, 2017
Hypertrophic cardiomyopathy (HCM) is a highly heterogeneous disease displaying considerable interfamilial and intrafamilial phenotypic variation, including disease severity, age of onset, and disease progression. This poorly understood variance raises the possibility of genetic modifier effects, particularly in MYBPC3-associated HCM.In a large consanguineous Chinese HCM family, we identified 8 members harboring the MYBPC3 c.3624delC (p.Lys1209Serfs) disease-causing mutation, but with very disparate phenotypes. Genotyping ruled out the modifying effect of previously described variants in renin-angiotensin-aldosterone system. Afterwards, we screened for modifying variants in all known causing genes and closely related genes for cardiomyopathy and channelopathy by performing targeted next-generation sequencing. For first time, we showed that a c.1598C>T (p.Ser533Leu) mutation in voltage-dependent l-type calcium channel subunit beta-2 (CACNB2) was present in all severely affected HCM patients, but not in those moderately affected or genotype-positive phenotype-negative patients. This CACNB2 p.Ser533Leu mutation is extremely conserved in evolution, and was not found in 550 healthy controls.Our results suggest that CACNB2 is a possible candidate genetic modifier of MYBPC3-associated familial HCM, but more genetic evidence and functional experiments are needed to confirm.
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23 MeSH Terms
Trafficking Ion Transporters to the Apical Membrane of Polarized Intestinal Enterocytes.
Engevik AC, Goldenring JR
(2018) Cold Spring Harb Perspect Biol 10:
MeSH Terms: Animals, Cell Membrane, Cell Polarity, Cystic Fibrosis Transmembrane Conductance Regulator, Cytoskeletal Proteins, Enterocytes, Humans, Ion Transport, Malabsorption Syndromes, Membrane Transport Proteins, Microvilli, Mucolipidoses, Myosin Heavy Chains, Myosin Type V, Protein Transport, Sodium-Hydrogen Exchanger 3
Show Abstract · Added April 18, 2017
Epithelial cells lining the gastrointestinal tract require distinct apical and basolateral domains to function properly. Trafficking and insertion of enzymes and transporters into the apical brush border of intestinal epithelial cells is essential for effective digestion and absorption of nutrients. Specific critical ion transporters are delivered to the apical brush border to facilitate fluid and electrolyte uptake. Maintenance of these apical transporters requires both targeted delivery and regulated membrane recycling. Examination of altered apical trafficking in patients with Microvillus Inclusion disease caused by inactivating mutations in MYO5B has led to insights into the regulation of apical trafficking by elements of the apical recycling system. Modeling of MYO5B loss in cell culture and animal models has led to recognition of Rab11a and Rab8a as critical regulators of apical brush border function. All of these studies show the importance of apical membrane trafficking dynamics in maintenance of polarized epithelial cell function.
Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.
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16 MeSH Terms
Myosin-7b Promotes Distal Tip Localization of the Intermicrovillar Adhesion Complex.
Weck ML, Crawley SW, Stone CR, Tyska MJ
(2016) Curr Biol 26: 2717-2728
MeSH Terms: Animals, Caco-2 Cells, Epithelial Cells, Humans, LLC-PK1 Cells, Microvilli, Myosin Heavy Chains, Swine
Show Abstract · Added April 7, 2017
Transporting epithelial cells interact with the luminal environment using a tightly packed array of microvilli known as the brush border. During intestinal epithelial differentiation, microvillar packing and organization are driven by cadherin-dependent adhesion complexes that localize to the distal tips of microvilli, where they drive physical interactions between neighboring protrusions. Although enrichment of the "intermicrovillar adhesion complex" (IMAC) at distal tips is required for proper function, the mechanism driving tip accumulation of these factors remains unclear. Here, we report that the actin-based motor myosin-7b (Myo7b) promotes the accumulation of IMAC components at microvillar tips. Myo7b is highly enriched at the tips of microvilli in both kidney and intestinal brush borders, and loss of Myo7b in differentiating intestinal epithelial cells disrupts intermicrovillar adhesion and, thus, brush border assembly. Analysis of cells lacking Myo7b revealed that IMAC components and the resulting intermicrovillar adhesion links are mislocalized along the microvillar axis rather than enriched at the distal tips. We also found that Myo7b motor domains are capable of supporting tip-directed transport. However, motor activity is supplemented by other passive targeting mechanisms that together drive highly efficient IMAC accumulation at the tips. These findings illuminate the molecular basis of IMAC enrichment at microvillar tips and hold important implications for understanding apical morphogenesis in transporting and sensory epithelial tissues.
Copyright © 2016 Elsevier Ltd. All rights reserved.
1 Communities
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8 MeSH Terms
Impact of the Motor and Tail Domains of Class III Myosins on Regulating the Formation and Elongation of Actin Protrusions.
Raval MH, Quintero OA, Weck ML, Unrath WC, Gallagher JW, Cui R, Kachar B, Tyska MJ, Yengo CM
(2016) J Biol Chem 291: 22781-22792
MeSH Terms: Actins, Animals, COS Cells, Cercopithecus aethiops, Humans, Myosin Heavy Chains, Myosin Type III, Pseudopodia
Show Abstract · Added April 7, 2017
Class III myosins (MYO3A and MYO3B) are proposed to function as transporters as well as length and ultrastructure regulators within stable actin-based protrusions such as stereocilia and calycal processes. MYO3A differs from MYO3B in that it contains an extended tail domain with an additional actin-binding motif. We examined how the properties of the motor and tail domains of human class III myosins impact their ability to enhance the formation and elongation of actin protrusions. Direct examination of the motor and enzymatic properties of human MYO3A and MYO3B revealed that MYO3A is a 2-fold faster motor with enhanced ATPase activity and actin affinity. A chimera in which the MYO3A tail was fused to the MYO3B motor demonstrated that motor activity correlates with formation and elongation of actin protrusions. We demonstrate that removal of individual exons (30-34) in the MYO3A tail does not prevent filopodia tip localization but abolishes the ability to enhance actin protrusion formation and elongation in COS7 cells. Interestingly, our results demonstrate that MYO3A slows filopodia dynamics and enhances filopodia lifetime in COS7 cells. We also demonstrate that MYO3A is more efficient than MYO3B at increasing formation and elongation of stable microvilli on the surface of cultured epithelial cells. We propose that the unique features of MYO3A, enhanced motor activity, and an extended tail with tail actin-binding motif, allow it to play an important role in stable actin protrusion length and ultrastructure maintenance.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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8 MeSH Terms
A small part of myosin IIB takes on a big role in cell polarity.
Fenix AM, Burnette DT
(2015) J Cell Biol 209: 11-2
MeSH Terms: Animals, Cell Polarity, Humans, Myosin Heavy Chains, Nonmuscle Myosin Type IIB
Show Abstract · Added August 25, 2017
A migrating cell must establish front-to-back polarity in order to move. In this issue, Juanes-Garcia et al. (2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201407059) report that a short serine-rich motif in nonmuscle myosin IIB is required to establish the cell's rear. This motif represents a new paradigm for what determines directional cell migration.
© 2015 Fenix and Burnette.
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5 MeSH Terms
Shaping the intestinal brush border.
Crawley SW, Mooseker MS, Tyska MJ
(2014) J Cell Biol 207: 441-51
MeSH Terms: Animals, Cell Differentiation, Cytoskeletal Proteins, Cytoskeleton, Enterocytes, Humans, Intestines, Mice, Microvilli, Myosin Heavy Chains, Myosin Type I
Show Abstract · Added January 21, 2015
Epithelial cells from diverse tissues, including the enterocytes that line the intestinal tract, remodel their apical surface during differentiation to form a brush border: an array of actin-supported membrane protrusions known as microvilli that increases the functional capacity of the tissue. Although our understanding of how epithelial cells assemble, stabilize, and organize apical microvilli is still developing, investigations of the biochemical and physical underpinnings of these processes suggest that cells coordinate cytoskeletal remodeling, membrane-cytoskeleton cross-linking, and extracellular adhesion to shape the apical brush border domain.
© 2014 Crawley et al.
1 Communities
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11 MeSH Terms
Myosin Vb uncoupling from RAB8A and RAB11A elicits microvillus inclusion disease.
Knowles BC, Roland JT, Krishnan M, Tyska MJ, Lapierre LA, Dickman PS, Goldenring JR, Shub MD
(2014) J Clin Invest 124: 2947-62
MeSH Terms: Caco-2 Cells, Enterocytes, Gene Knockdown Techniques, Humans, Indians, North American, Infant, Malabsorption Syndromes, Microvilli, Mucolipidoses, Mutation, Myosin Heavy Chains, Myosin Type V, RNA, Small Interfering, rab GTP-Binding Proteins
Show Abstract · Added July 31, 2014
Microvillus inclusion disease (MVID) is a severe form of congenital diarrhea that arises from inactivating mutations in the gene encoding myosin Vb (MYO5B). We have examined the association of mutations in MYO5B and disruption of microvillar assembly and polarity in enterocytes. Stable MYO5B knockdown (MYO5B-KD) in CaCo2-BBE cells elicited loss of microvilli, alterations in junctional claudins, and disruption of apical and basolateral trafficking; however, no microvillus inclusions were observed in MYO5B-KD cells. Expression of WT MYO5B in MYO5B-KD cells restored microvilli; however, expression of MYO5B-P660L, a MVID-associated mutation found within Navajo populations, did not rescue the MYO5B-KD phenotype but induced formation of microvillus inclusions. Microvilli establishment required interaction between RAB8A and MYO5B, while loss of the interaction between RAB11A and MYO5B induced microvillus inclusions. Using surface biotinylation and dual immunofluorescence staining in MYO5B-KD cells expressing mutant forms of MYO5B, we observed that early microvillus inclusions were positive for the sorting marker SNX18 and derived from apical membrane internalization. In patients with MVID, MYO5B-P660L results in global changes in polarity at the villus tips that could account for deficits in apical absorption, loss of microvilli, aberrant junctions, and losses in transcellular ion transport pathways, likely leading to the MVID clinical phenotype of neonatal secretory diarrhea.
1 Communities
3 Members
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14 MeSH Terms
Motor and tail homology 1 (Th1) domains antagonistically control myosin-1 dynamics.
Mazerik JN, Kraft LJ, Kenworthy AK, Tyska MJ
(2014) Biophys J 106: 649-58
MeSH Terms: Actin Cytoskeleton, Actins, Animals, Cell Line, Cell Membrane, Mutation, Myosin Heavy Chains, Myosin Type I, Protein Binding, Protein Isoforms, Protein Structure, Tertiary, Protein Transport, Swine
Show Abstract · Added May 19, 2014
Class 1 myosins are monomeric motor proteins that fulfill diverse functions at the membrane/cytoskeletal interface. All myosins-1 contain a motor domain, which binds actin, hydrolyzes ATP, and generates forces, and a TH1 domain, which interacts directly with membrane lipids. In most cases, TH1 is needed for proper subcellular localization and presumably function, although little is known about how this domain regulates the behavior of class 1 myosins in live cells. To address this, we used single molecule total internal reflection fluorescence microscopy to examine the dynamics of the well-characterized myosin-1a isoform during interactions with the cortex of living cells. Our studies revealed that full-length myosin-1a exhibits restricted mobility relative to TH1 alone. Motor domain mutations that disrupt actin binding increased the mobility of full-length myosin-1a, whereas mutations to the TH1 domain that are known to reduce steady-state targeting to the plasma membrane unexpectedly reduced mobility. Deletion of the calmodulin-binding lever arm in Myo1a mimicked the impact of actin-binding mutations. Finally, myosin-1b, which demonstrates exquisite sensitivity to mechanical load, exhibited dynamic behavior nearly identical to myosin-1a. These studies are the first, to our knowledge, to explore class 1 myosin dynamics at the single-molecule level in living cells; our results suggest a model where the motor domain restricts dynamics via a mechanism that requires the lever arm, whereas the TH1 domain allows persistent diffusion in close proximity to the plasma membrane.
Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.
1 Communities
2 Members
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13 MeSH Terms
Rab11-FIP2 interaction with MYO5B regulates movement of Rab11a-containing recycling vesicles.
Schafer JC, Baetz NW, Lapierre LA, McRae RE, Roland JT, Goldenring JR
(2014) Traffic 15: 292-308
MeSH Terms: Animals, Binding Sites, Carrier Proteins, Dogs, Endosomes, HeLa Cells, Humans, Madin Darby Canine Kidney Cells, Membrane Proteins, Myosin Heavy Chains, Myosin Type V, Point Mutation, Protein Binding, Protein Transport, rab GTP-Binding Proteins
Show Abstract · Added March 10, 2014
A tripartite association of Rab11a with both Rab11-FIP2 and MYO5B regulates recycling endosome trafficking. We sought to define the intermolecular interactions required between Rab11-FIP2 and MYO5B. Using a random mutagenesis strategy, we identified point mutations at S229P or G233E in Rab11-FIP2 that caused loss of interaction with MYO5B in yeast two-hybrid assays as well as loss of interaction of Rab11-FIP2(129-356) with MYO5B tail when expressed in HeLa cells. Single mutations or the double S229P/G233E mutation failed to alter the association of full-length Rab11-FIP2 with MYO5B tail in HeLa cells. While EGFP-Rab11-FIP2 wild type colocalized with endogenous MYO5B staining in MDCK cells, EGFP-Rab11-FIP2(S229P/G233E) showed a significant decrease in localization with endogenous MYO5B. Analysis of Rab11a-containing vesicle movement in live HeLa cells demonstrated that when the MYO5B/Rab11-FIP2 association is perturbed by mutation or by Rab11-FIP2 knockdown, vesicle movement is increased in both speed and track length, consistent with an impairment of MYO5B tethering at the cytoskeleton. These results support a critical role for the interaction of MYO5B with Rab11-FIP2 in stabilizing the functional complex with Rab11a, which regulates dynamic movements of membrane recycling vesicles.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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15 MeSH Terms