Regulation of protrusion, adhesion dynamics, and polarity by myosins IIA and IIB in migrating cells

Vicente‐Manzanares, Miguel; Zareno, Jessica; Whitmore, Leanna; Choi, Colin; Horwitz, Alan F.

doi:10.1083/jcb.200612043

Cited by 375 publications

(465 citation statements)

References 42 publications

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“…This view is supported by the recent report showing that the expressed MHC-IIB, in which the PKC phosphorylation sites were converted to Asp residues, was able to localize at the stress fibers, but this mutation attenuated the localization of the mutant MHC-IIB to the cell cortex (Rosenberg and Ravid, 2006). Moreover, it was recently reported that myosin II isoforms (IIA and IIB) differentially contributes to the cell motility (Even-Ram et al, 2007;Vicente-Manzanares et al, 2007), suggesting that myosin isoforms are regulated by distinct mechanisms in motile cells. Supporting this notion, biochemical studies revealed that phosphate incorporation of MHC-IIB by PKC is much faster than that of myosin IIA and, in contrast, that filament assembly of myosin IIA is regulated by its binding protein (Mts1) but not that of myosin IIB (Murakami et al, 1998(Murakami et al, , 2000Dulyaninova et al, 2005).…”

Section: Discussionsupporting

confidence: 71%

The Phosphorylation of Myosin II at the Ser1 and Ser2 Is Critical for Normal Platelet-derived Growth Factor–induced Reorganization of Myosin Filaments

Komatsu

Ikebe

2007

MBoC

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Phosphorylation of the regulatory light chain of myosin II (MLC 20 ) at the activation sites promotes both the motor activity and the filament formation of myosin II, thus playing an important role in various cell motile processes. In contrast, the physiological function of phosphorylation of MLC 20 at the inhibitory sites is unknown. Here we report for the first time the function of the inhibitory site phosphorylation in the cells. We successfully produced the antibodies specifically recognizing the phosphorylation sites of MLC 20 at Ser1, and the platelet-derived growth factor (PDGF)-induced change in the phosphorylation at the Ser1 was monitored. The phosphorylation of MLC 20 at the Ser1 significantly increased during the PDGF-induced actin cytoskeletal reorganization. PDGF disassembled the stress fibers, and this was attenuated with the expression of unphosphorylatable MLC 20 at the Ser1/Ser2 phosphorylation sites. The present results suggest that the down-regulation of myosin II activity achieved by the phosphorylation at the Ser1/Ser2 sites plays an important role in the normal reorganization of actomyosin filaments triggered by PDGF receptor stimulation. INTRODUCTIONCell migration plays a key role in both the physiological and the pathophysiological function of the cells including development, wound healing, immunity, and metastasis (Lauffenburger and Horwitz, 1996). Reorganization of actomyosin filaments is an essential process for these cell behaviors. It has been thought that myosin II plays a fundamental role in various types of cellular motility.In vitro biochemical studies have revealed that the function of smooth muscle and nonmuscle myosin II is regulated by the phosphorylation of MLC 20 (Sellers, 1991;Tan et al., 1992). A number of studies have shown that the phosphorylation of MLC 20 at Thr18 and Ser19 activates its motor activity and increases filament stability. On the other hand, it has been known that MLC 20 can be phosphorylated at other sites different from the activation sites. Originally, it was found that protein kinase C (PKC) phosphorylates Ser1/Ser2 and Thr9 of MLC 20 . This phosphorylation decreases the affinity of myosin II phosphorylated at the activation sites for actin and the affinity of MLC 20 for myosin light-chain kinase (MLCK; Nishikawa et al., 1984;Bengur et al., 1987;Ikebe et al., 1987;Ikebe and Reardon, 1990). In other words, the phosphorylation of MLC 20 at these sites inhibits rather than activates myosin II.It was reported that the phosphorylation of MLC 20 at the Thr9 inhibits myosin II motor activity and the phosphorylation of MLC 20 by MLCK (Nishikawa et al., 1984;Turbedsky et al., 1997); however, phosphorylation of the inhibitory sites in nonmuscle cells has only been observed on Ser1 and/or Ser2, but not on Thr9 in vivo (Kawamoto et al., 1989;Yamakita et al., 1994), and this is because the Ser1/Ser2 sites are resistant to dephosphorylation by myosin light chain phosphatases while phospho-Thr9 is readily dephosphorylated (Ikebe et al., 1999). Furthermore, it has b...

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Section: Discussionsupporting

confidence: 71%

The Phosphorylation of Myosin II at the Ser1 and Ser2 Is Critical for Normal Platelet-derived Growth Factor–induced Reorganization of Myosin Filaments

Komatsu

Ikebe

2007

MBoC

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“…Myosins IIA and IIB both contribute to the process of cell migration (Kolega, 2006;Ma et al, 2006;Vincente-Manzanares et al, 2007), and in breast carcinoma cells, they have distinct roles (Betapudi et al, 2006). The enzymatic activity of each of the myosin II isoforms is controlled by phosphorylation of the regulatory light chain (RLC), a process largely catalyzed by two regulatory kinases-myosin light chain kinase and rho kinase (Tan et al, 1992;Amano et al, 1996).…”

Section: Myosin II Isoform Expression In Gliomasmentioning

confidence: 99%

The Role of Myosin II in Glioma Invasion of the Brain

Beadle

Assanah

Monzo

et al. 2008

MBoC

292

334

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The ability of gliomas to invade the brain limits the efficacy of standard therapies. In this study, we have examined glioma migration in living brain tissue by using two novel in vivo model systems. Within the brain, glioma cells migrate like nontransformed, neural progenitor cells-extending a prominent leading cytoplasmic process followed by a burst of forward movement by the cell body that requires myosin II. In contrast, on a two-dimensional surface, glioma cells migrate more like fibroblasts, and they do not require myosin II to move. To explain this phenomenon, we studied glioma migration through a series of synthetic membranes with defined pore sizes. Our results demonstrate that the A and B isoforms of myosin II are specifically required when a glioma cell has to squeeze through pores smaller than its nuclear diameter. They support a model in which the neural progenitor-like mode of glioma invasion and the requirement for myosin II represent an adaptation needed to move within the brain, which has a submicrometer effective pore size. Furthermore, the absolute requirement for myosin II in brain invasion underscores the importance of this molecular motor as a potential target for new anti-invasive therapies to treat malignant brain tumors. INTRODUCTIONMalignant gliomas are a group of primary brain tumors that have remained resistant to therapy and that have a dismal prognosis (Buckner et al., 2007;Stupp et al., 2007). Part of the reason for this state of affairs is that although gliomas rarely metastasize outside the CNS, they are capable of spreading long distances within the brain (Sherer, 1940;Burger and Kleihues, 1989;Hoelzinger et al., 2007). This invasive behavior limits the effectiveness of local therapies and contributes to the high mortality rate seen in these tumors (Lim et al., 2007). Preventing glioma invasion therefore has the potential to convert this highly malignant tumor into a focal disease, which could then be effectively treated with focal therapies, such as radiation and surgery. Realizing this outcome, however, will require a detailed understanding how gliomas invade normal brain.Gliomas typically invade the brain by migrating long distances through white matter tracts and by infiltrating cortex and subcortical gray matter structures. Brain parenchyma (neuropil) is composed of tightly packed neuronal and glial processes, and it is characterized by extracellular spaces that are in the submicrometer range (Thorne and Nicholson, 2006). This environment therefore represents a particular mechanical challenge to motile cells, such as gliomas, that need to insinuate themselves through a highly constraining brain matrix to migrate. Unfortunately, there is very little information about how glioma cells accomplish this process in vivo. Some insight is provided by studies of embryonic and early postnatal brain, where neural progenitor cells migrate along radial glial cells, and to some extent through the white matter and cortex before stopping and differentiating into mature neurons and glia. Ti...

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“…Nonmuscle myosin (NM) II, one of the major cytoskeletal motor proteins, plays an important role in cell migration (Svitkina et al, 1997;Ma et al, 2004;Even-Ram et al, 2007;Vicente-Manzanares et al, 2007), cell-cell adhesion Shewan et al, 2005;Giannone et al, 2007), and cell division (De Lozanne and Spudich, 1987;Takeda et al, 2003;Bao et al, 2005). The molecular structure of NM II is a hexamer consisting of a pair of myosin heavy chains (200 kDa) and two pairs of light chains (20 and 17 kDa).…”

Section: Introductionmentioning

confidence: 99%

“…The defect may be accompanied by an obstructed aqueduct of Sylvius, the narrow channel connecting the third and fourth brain ventricles (noncommunicating hydrocephalus), or by a normal aqueduct (communicating hydrocephalus). The pathogenesis of most cases of communicating hydrocephalus is largely unknown (for reviews, see Perez-Figares et al, 2001;Crews et al, 2004).Nonmuscle myosin (NM) II, one of the major cytoskeletal motor proteins, plays an important role in cell migration (Svitkina et al, 1997;Ma et al, 2004;Even-Ram et al, 2007;Vicente-Manzanares et al, 2007), cell-cell adhesion Shewan et al, 2005;Giannone et al, 2007), and cell division (De Lozanne and Spudich, 1987;Takeda et al, 2003;Bao et al, 2005). The molecular structure of NM II is a hexamer consisting of a pair of myosin heavy chains (200 kDa) and two pairs of light chains (20 and 17 kDa).…”

mentioning

confidence: 99%

Loss of Cell Adhesion Causes Hydrocephalus in Nonmuscle Myosin II-B–ablated and Mutated Mice

Bao

Adelstein

2007

MBoC

103

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Ablation of nonmuscle myosin (NM) II-B in mice during embryonic development leads to marked enlargement of the cerebral ventricles and destruction of brain tissue, due to hydrocephalus. We have identified a transient mesh-like structure present at the apical border of cells lining the spinal canal of mice during development. This structure, which only contains the II-B isoform of NM, also contains ␤-catenin and N-cadherin, consistent with a role in cell adhesion. Ablation of NM II-B or replacement of NM II-B with decreased amounts of a mutant (R709C), motor-impaired NM II-B in mice results in collapse of the mesh-like structure and loss of cell adhesion. This permits the underlying neuroepithelial cells to invade the spinal canal and obstruct cerebral spinal fluid flow. These defects in the CNS of NM II-B-ablated mice seem to be the cause of hydrocephalus. Interestingly, the mesh-like structure and patency of the spinal canal can be restored by increasing expression of the motor-impaired NM II-B, which also rescues hydrocephalus. However, the mutant isoform cannot completely rescue neuronal cell migration. These studies show that the scaffolding properties of NM II-B play an important role in cell adhesion, thereby preventing hydrocephalus during mouse brain development. INTRODUCTIONCongenital hydrocephalus affects one to three humans per 1000 live births. The results of this abnormality can be devastating in that severe, untreated hydrocephalus can destroy brain tissue and thereby lead to mental retardation. Hydrocephalus occurs when there is an increase in pressure in the ventricular chambers due to a blockage in the circulation of cerebral spinal fluid (CSF) or when there is an increase in production or decrease in the absorption of the CSF. The defect may be accompanied by an obstructed aqueduct of Sylvius, the narrow channel connecting the third and fourth brain ventricles (noncommunicating hydrocephalus), or by a normal aqueduct (communicating hydrocephalus). The pathogenesis of most cases of communicating hydrocephalus is largely unknown (for reviews, see Perez-Figares et al., 2001;Crews et al., 2004).Nonmuscle myosin (NM) II, one of the major cytoskeletal motor proteins, plays an important role in cell migration (Svitkina et al., 1997;Ma et al., 2004;Even-Ram et al., 2007;Vicente-Manzanares et al., 2007), cell-cell adhesion Shewan et al., 2005;Giannone et al., 2007), and cell division (De Lozanne and Spudich, 1987;Takeda et al., 2003;Bao et al., 2005). The molecular structure of NM II is a hexamer consisting of a pair of myosin heavy chains (200 kDa) and two pairs of light chains (20 and 17 kDa). In mammals, three isoforms of the nonmuscle myosin heavy chain (NMHC) have been identified, NMHC II-A, II-B, and II-C, encoded by three different genes, Myh 9, Myh 10, and Myh 14 in humans. The NMHCs share a 60 -80% identity in amino acids, but they show significant differences in their motor activities (Golomb et al., 2004;Kim et al., 2005). In general, all three isoforms are ubiquitously expressed in vertebrat...

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Regulation of protrusion, adhesion dynamics, and polarity by myosins IIA and IIB in migrating cells

Cited by 375 publications

References 42 publications

The Phosphorylation of Myosin II at the Ser1 and Ser2 Is Critical for Normal Platelet-derived Growth Factor–induced Reorganization of Myosin Filaments

The Phosphorylation of Myosin II at the Ser1 and Ser2 Is Critical for Normal Platelet-derived Growth Factor–induced Reorganization of Myosin Filaments

The Role of Myosin II in Glioma Invasion of the Brain

Loss of Cell Adhesion Causes Hydrocephalus in Nonmuscle Myosin II-B–ablated and Mutated Mice

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