Tyrosine Phosphorylation of the Myosin Regulatory Light Chain Controls Non-muscle Myosin II Assembly and Function in Migrating Cells

Aguilar-Cuenca, Rocío; Llorente-González, Clara; Chapman, Jessica R.; Talayero, Vanessa C.; Garrido-Casado, Marina; Delgado‐Arévalo, Cristina; Millán-Salanova, María; Shabanowitz, Jeffrey; Hunt, Donald F.; Sellers, James R.; Heissler, Sarah M.; Vicente‐Manzanares, Miguel

doi:10.1016/j.cub.2020.04.057

Cited by 22 publications

(26 citation statements)

References 59 publications

(70 reference statements)

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“…In mesenchymal cells, this mechanism prevents actomyosin assembly at the leading edge during chemotaxis [69]. Finally, phosphorylation of Tyr155 has been recently described to regulate NMII assembly through a different mechanism, which controls the formation of the NMII hexamer by impairing the interaction of the RLC with the heavy chain when Tyr155 is phosphorylated [70].…”

Section: Regulation Of the Conforzmation Of Nmii-a And Its Atpase Actmentioning

confidence: 99%

Linking the Landscape of MYH9-Related Diseases to the Molecular Mechanisms that Control Non-Muscle Myosin II-A Function in Cells

Asensio-Juárez

Llorente-González

Vicente‐Manzanares

2020

Cells

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The MYH9 gene encodes the heavy chain (MHCII) of non-muscle myosin II A (NMII-A). This is an actin-binding molecular motor essential for development that participates in many crucial cellular processes such as adhesion, cell migration, cytokinesis and polarization, maintenance of cell shape and signal transduction. Several types of mutations in the MYH9 gene cause an array of autosomal dominant disorders, globally known as MYH9-related diseases (MYH9-RD). These include May-Hegglin anomaly (MHA), Epstein syndrome (EPS), Fechtner syndrome (FTS) and Sebastian platelet syndrome (SPS). Although caused by different MYH9 mutations, all patients present macrothrombocytopenia, but may later display other pathologies, including loss of hearing, renal failure and presenile cataracts. The correlation between the molecular and cellular effects of the different mutations and clinical presentation are beginning to be established. In this review, we correlate the defects that MYH9 mutations cause at a molecular and cellular level (for example, deficient filament formation, altered ATPase activity or actin-binding) with the clinical presentation of the syndromes in human patients. We address why these syndromes are tissue restricted, and the existence of possible compensatory mechanisms, including residual activity of mutant NMII-A and/or the formation of heteropolymers or co-polymers with other NMII isoforms.

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Section: Regulation Of the Conforzmation Of Nmii-a And Its Atpase Actmentioning

confidence: 99%

Linking the Landscape of MYH9-Related Diseases to the Molecular Mechanisms that Control Non-Muscle Myosin II-A Function in Cells

Asensio-Juárez

Llorente-González

Vicente‐Manzanares

2020

Cells

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“…Myosin II function is also controlled by phosphorylation of the RLC in Ser1, which decreases its affinity for actin and its ATPase activity [228]. Phosphorylation of Tyr155 downstream of the RTKs also impairs the formation of the functional hexamer [229]. Finally, myosin II assembly is also regulated by phosphorylation of the coiled-coil and non-helical tail domain.…”

Section: Myosin II As An Endpoint Of Chemical and Mechanical Signalingmentioning

confidence: 99%

The Crossroads between RAS and RHO Signaling Pathways in Cellular Transformation, Motility and Contraction

Soriano

Alcón-Pérez

Vicente‐Manzanares

et al. 2021

Genes

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Ras and Rho proteins are GTP-regulated molecular switches that control multiple signaling pathways in eukaryotic cells. Ras was among the first identified oncogenes, and it appears mutated in many forms of human cancer. It mainly promotes proliferation and survival through the MAPK pathway and the PI3K/AKT pathways, respectively. However, the myriad proteins close to the plasma membrane that activate or inhibit Ras make it a major regulator of many apparently unrelated pathways. On the other hand, Rho is weakly oncogenic by itself, but it critically regulates microfilament dynamics; that is, actin polymerization, disassembly and contraction. Polymerization is driven mainly by the Arp2/3 complex and formins, whereas contraction depends on myosin mini-filament assembly and activity. These two pathways intersect at numerous points: from Ras-dependent triggering of Rho activators, some of which act through PI3K, to mechanical feedback driven by actomyosin action. Here, we describe the main points of connection between the Ras and Rho pathways as they coordinately drive oncogenic transformation. We emphasize the biochemical crosstalk that drives actomyosin contraction driven by Ras in a Rho-dependent manner. We also describe possible routes of mechanical feedback through which myosin II activation may control Ras/Rho activation.

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“…A fine balance between myosin kinases and phosphatases determines the extent of myosin activation at the right place and time ( Figure 5 ). A novel regulatory phosphorylation on RLC Tyrosine 155 (Tyr 155) was recently demonstrated to spatially control the assembly and function of NM2 in migrating cells [ 73 ]. This phosphorylation is mediated by epidermal growth factor receptor (EGFR) and impairs the interaction between NMHC2s and RLCs, specifically at migratory cell protrusions, restricting the assembly of functional NM2 molecules [ 73 ].…”

Section: Nm2a Regulationmentioning

confidence: 99%

“…A novel regulatory phosphorylation on RLC Tyrosine 155 (Tyr 155) was recently demonstrated to spatially control the assembly and function of NM2 in migrating cells [ 73 ]. This phosphorylation is mediated by epidermal growth factor receptor (EGFR) and impairs the interaction between NMHC2s and RLCs, specifically at migratory cell protrusions, restricting the assembly of functional NM2 molecules [ 73 ]. Given that the majority of Tyr kinases are negatively regulated and only activated in very specific conditions [ 74 ], it is tempting to speculate that other unexplored NM2 Tyr phosphorylations, either on the light or the heavy chains, further regulate its assembly, localization and function.…”

Section: Nm2a Regulationmentioning

confidence: 99%

Non-Muscle Myosin 2A (NM2A): Structure, Regulation and Function

Brito

Sousa

2020

Cells

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Non-muscle myosin 2A (NM2A) is a motor cytoskeletal enzyme with crucial importance from the early stages of development until adulthood. Due to its capacity to convert chemical energy into force, NM2A powers the contraction of the actomyosin cytoskeleton, required for proper cell division, adhesion and migration, among other cellular functions. Although NM2A has been extensively studied, new findings revealed that a lot remains to be discovered concerning its spatiotemporal regulation in the intracellular environment. In recent years, new functions were attributed to NM2A and its activity was associated to a plethora of illnesses, including neurological disorders and infectious diseases. Here, we provide a concise overview on the current knowledge regarding the structure, the function and the regulation of NM2A. In addition, we recapitulate NM2A-associated diseases and discuss its potential as a therapeutic target.

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Tyrosine Phosphorylation of the Myosin Regulatory Light Chain Controls Non-muscle Myosin II Assembly and Function in Migrating Cells

Abstract: Highlights d Myosin light chain (RLC) is phosphorylated in tyrosine d Aberrant cell function by RLC deletion is not corrected by phospho-mimetic RLC d Phosphorylation of RLC in Y155 impairs formation of functional myosin hexamers d Phospho-Y155 RLC mainly appears at lamellipodia

Cited by 22 publications

References 59 publications

Linking the Landscape of MYH9-Related Diseases to the Molecular Mechanisms that Control Non-Muscle Myosin II-A Function in Cells

Linking the Landscape of MYH9-Related Diseases to the Molecular Mechanisms that Control Non-Muscle Myosin II-A Function in Cells

The Crossroads between RAS and RHO Signaling Pathways in Cellular Transformation, Motility and Contraction

Non-Muscle Myosin 2A (NM2A): Structure, Regulation and Function

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