PAK1 and aPKCζ Regulate Myosin II-B Phosphorylation: A Novel Signaling Pathway Regulating Filament Assembly

Even-Faitelson, Liron; Ravid, Shoshana

doi:10.1091/mbc.e05-11-1001

Cited by 93 publications

(86 citation statements)

References 50 publications

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“…44,47 Moreover, different signaling pathways control the assembly of each myosin II isoform as the kinetics of myosins IIA and IIB phosphorylation upon agonist stimulation of mammalian cells differ and separate members of the PKC family, specifically, phosphorylated myosins IIA and IIB. 26,27,45 We conclude that both myosins IIA and IIB are regulated by heavy chain phosphorylation in vivo but that specific signaling pathways control the assembly of these different myosin II isoforms.…”

Section: Discussionmentioning

confidence: 85%

“…In fact, detecting the phosphorylation of a particular site on myosin II generally requires the mutation of several residues that are phosphorylated by other kinases. 27 Moreover, the TRPM7 kinase is low in abundance relative to other kinases. Based on the low expression levels, we do not believe that TRPM7 is responsible for the global regulation of myosin IIA dynamics in mammalian cells and that additional mechanisms are in place for this purpose.…”

Section: Discussionmentioning

confidence: 99%

“…However, strong experimental evidence exists for additional regulatory mechanisms, including myosin II heavy chain (MHCII) phosphorylation. [24][25][26][27] Recently, we identified a novel signaling pathway downstream of the bradykinin receptor that regulates myosin II-based contractility in nonmuscle cells. 28,29 Bradykinin stimulation of neuroblastoma cells activates TRPM7, promoting its association with myosin IIA in a Ca 2+ -and kinase-dependent manner, which leads to actomyosin relaxation and remodeling of cell adhesion structures.…”

Section: Introductionmentioning

confidence: 99%

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TRPM7 Regulates Myosin IIA Filament Stability and Protein Localization by Heavy Chain Phosphorylation

Clark

Middelbeek

Lasonder

et al. 2008

Journal of Molecular Biology

123

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Deregulation of myosin II-based contractility contributes to the pathogenesis of human diseases, such as cancer, which underscores the necessity for tight spatial and temporal control of myosin II activity. Recently, we demonstrated that activation of the mammalian α-kinase TRPM7 inhibits myosin II-based contractility in a Ca 2+ -and kinase-dependent manner. However, the molecular mechanism is poorly defined. Here, we demonstrate that TRPM7 phosphorylates the COOHtermini of both mouse and human myosin IIA heavy chains-the COOH-terminus being a region that is critical for filament stability. Phosphorylated residues were mapped to Thr1800, Ser1803 and Ser1808. Mutation of these residues to alanine and that to aspartic acid lead to an increase and a decrease, respectively, in myosin IIA incorporation into the actomyosin cytoskeleton and accordingly affect subcellular localization. In conclusion, our data demonstrate that TRPM7 regulates myosin IIA filament stability and localization by phosphorylating a short stretch of amino acids within the α-helical tail of the myosin IIA heavy chain.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TRPM7 Regulates Myosin IIA Filament Stability and Protein Localization by Heavy Chain Phosphorylation

Clark

Middelbeek

Lasonder

et al. 2008

Journal of Molecular Biology

123

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“…Although it is possible that NMHC II-B serves as a downstream target of aPKC in regulating cell adhesion in the spinal canal, there are other putative targets in the neuronal adherens junction as well, such as PAR3 and Lgl1 (Yamanaka et al, 2003;Klezovitch et al, 2004;Suzuki and Ohno, 2006;Vasioukhin, 2006). In contrast, Even-Faitelson and Ravid (2006) have reported that phosphorylation of the NMHC II-B in the nonhelical tail by an aPKC results in cortical localization of both NM II-B and aPKC in a prostate cancer cell line. The requirement of aPKC in cell-cell adhesion has been demonstrated both in cultured cells (Suzuki et al, 2001, Nunbhakdi-Craig et al, 2002 and neuroepithelial cells in the developing mouse brain (Manabe et al, 2002).…”

Section: Cell-cell Adhesion Of the Neuroepithelial Cells Requires Nonmentioning

confidence: 98%

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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“…While HC phosphorylations at multiple sites modulate M2B filament formation (Murakami et al 2000;Even-Faitelson and Ravid 2006), metastasis-associated protein, S100A4 (a.k.a. Mts1), binds to the C-terminal end of the α-helical tail of M2A in a calcium-dependent manner and blocks the critical filament assembly site including the site for PKCβII phosphorylation at Ser1917, directly inhibiting filament assembly and leading to an inhibition of MgATPase activity (Ford et al 1997;Kriajevska et al 1998;Li and Bresnick 2006).…”

Section: The Players: Binding Partners and Regulationmentioning

confidence: 99%

Conventional myosins – unconventional functions

et al. 2010

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While the discovery of unconventional myosins raised expectations that their actions were responsible for most aspects of actin-based cell motility, few anticipated the wide range of cellular functions that would remain the purview of conventional two-headed myosins. The three nonsarcomeric, cellular myosins-M2A, M2B and M2C-participate in diverse roles including, but not limited to: neuronal dynamics, axon guidance and synaptic transmission; endothelial cell migration; cell adhesion, polarity, fusion and cytokinesis; vesicle trafficking and viral egress. These three conventional myosins each take on specific, differing functional roles during development and maturity, characteristic of each cell lineage; exact roles depend on the developmental stage of the cell, cellular location, upstream regulatory controls, relative isoform expression, orientation and associated state of the actin cytoscaffolds in which these myosins operate. Here, we discuss the separate yet related roles that characterise the actions of M2A, M2B and M2C in various cell types and show that these conventional myosins are responsible for functions as unconventional as any performed by unconventional myosins.

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PAK1 and aPKCζ Regulate Myosin II-B Phosphorylation: A Novel Signaling Pathway Regulating Filament Assembly

Cited by 93 publications

References 50 publications

TRPM7 Regulates Myosin IIA Filament Stability and Protein Localization by Heavy Chain Phosphorylation

TRPM7 Regulates Myosin IIA Filament Stability and Protein Localization by Heavy Chain Phosphorylation

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

Conventional myosins – unconventional functions

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