Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Nonmuscle Myosin II

  • Alba Juanes-García
  • Clara Llorente-González
  • Miguel Vicente-Manzanares
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101734


Heavy chain:  NMMHC-II;  MHCII; zipper (in Drosophila). Three isoforms are expressed in mammalian cells, also known as: (1) MHCII-A; myosin-9= MHA= FTNS= EPSTS= BDPLT6= DFNA17= NMMHCA= NMHC-II-A= NMMHC-IIA; (2) MHCII-B=myosin-10= NMMHCB= NMMHC-IIB; (3) MHCII-C=myosin-14= DFNA4= DFNA4A= FP17425= MHC16= MYH17= NMHC II-C= NMHC-II-C= PNMHH= myosin. Arabic numbers are now used too, e.g., myosin 2

Regulatory light chain:  RLC;  MLC;  MRLC;  MYRL; spaghetti squash (in Drosophila). Three isoforms are expressed in mammalian cells, also known as: (1) SM (smooth muscle)-RLC= MYL9= LC20= MLC-2C= MLC2= MRLC1= MYRL2; (2) MYL12A= HEL-S-24= MLC-2B= MLCB= MRCL3= MRLC3= MYL2B; (3) MYL12B= MLC-B=MRLC2

Essential light chain: MYL6= ELC= MLC= MLC-ALK= MLC1 (in Drosophila)

Functional unit (2×HC+2×RLC+2×ELC): NMII, NMMII, cytoplasmic myosin II

Historical Background

The discovery of nonmuscle myosin II (NMII) is linked to the story of muscle contraction (reviewed in Szent-Gyorgyi 2004). It started in 1864, when Köhler purified a viscous substance (“myosin”) from muscle, which he thought related to the contractile properties of muscle. In 1939, myosin was identified as an ATPase made of two major components, myosin and actomyosin. This led to the seminal idea that myosin and actin formed two types of interacting filaments. In the 1950s, proteolytic studies revealed the main functional parts of myosin: a heavy meromyosin that interacted with actin and contained the ATPase activity and a light meromyosin that enabled the formation of myosin filaments. The myosin light chains were also identified around this time. These experiments, together with crystallographic and functional evidence of the different bands that comprise the muscle sarcomere, allowed Huxley to propose that muscle contraction was due to the sliding of actin and myosin filaments with respect to each other. The concept that myosin and ATP existed in different binding states was incorporated into this early model to formulate the myosin swinging cross-bridge model, which is the core of the function of muscle (and nonmuscle) myosin II activity (Huxley 1969). This model was the culmination of a hundred years of investigation, and it also spurred the interest of many cell biologists and physiologists in contractile events observed in nonmuscle cells, for example migrating cells and clot formation and retraction, and also in morphogenetic movements, for example gastrulation. This led to the rapid identification of nonmuscle myosin II (NMII) in platelets (Adelstein et al. 1971) and also in amoebae (Pollard and Korn 1973a, b). NMII is a ubiquitous protein expressed in all mammalian tissues as well as in simple organisms. Like muscle myosin II, NMII is endowed with ATPase activity and the ability to form filaments with actin. The main mechanism of action of NMII is also similar to that of muscle myosin II. It involves an ATP-powered conformational change of the myosin head (Spudich 2001). Such movement is conjoined with its interaction with actin. The conformational change of the myosin head while tethered to the actin produces the movement of the filament or exerts tension on it. This property has positioned NMII at the center of the mechanotransduction field as the major force and tension generator inside nonmuscle cells (Aguilar-Cuenca et al. 2014). In this chapter, we outline the major mechanisms controlling NMII ATPase and actin-binding activity and its assembly to form filaments as well as the emerging picture of downstream pathways that are regulated by NMII-generated mechanical force.

NMII Structure and Assembly

The multimolecular structure of NMII can be seen in Fig. 1. Briefly, the functional NMII unit comprises a hexamer made of two intertwined heavy chains (MHCII) that interact with each other through a long coiled-coil central domain. The actin-binding and Mg2+-actin-dependent ATPase (head) domain are located near the N-terminus. The head and coiled-coil domains are linked by a neck region that acts as a movable hinge during the conformational changes that support myosin head swinging. It also serves as the binding site of four light chains. Two of these chains (ELC) serve a structural purpose. The other two chains (RLC) control the ATPase function of the head domain of the heavy chain (see below). NMII exists in two conformations: an assembly-incompetent form, folded (10S) that can extend into an assembly-competent form (6S) that can bind actin (reviewed in detail in Cremo and Hartshorne (2007)). The 10S→6S conversion is regulated by an off/on switch in the regulatory chain constituted by two residues (Thr18/Ser19) that can be phosphorylated (ON) or not (OFF). This phosphorylation also promotes the ATPase activity of the heavy chain in the assembled form. Several kinases can phosphorylate one or both residues (see below). Additional mechanisms exist, for example phosphorylation of Ser1 and Ser2 by PKC. Only one isoform of the ELC has been described in mammals, encoded by Myl6, Gene ID: 4637, chromosome 12. (Note: All the gene identities and chromosome number correspond to the human molecules). Conversely, there are three mammalian variants of the RLC that can interact with NMII: one is the product of the gene Myl9 (Gene ID: 98932, chromosome 2), which encodes the smooth muscle variant of RLC; the other two are the products of the genes Myl12A (Gene ID: 10627, chromosome 18) and Myl12B (Gene ID: 103910, chromosome 18), which are bona fide nonmuscle RLCs. Finally, three mammalian isoforms of the heavy chain are encoded by different genes: Myh9 encodes the isoform II-A (Gene ID: 4627, chromosome 22); Myh10 encodes the isoform II-B (gene ID: 4628, chromosome 17); and Myh14 encodes the isoform II-C (Gene ID: 79784, chromosome 19). Nomenclature-wise, the heavy chain isoform determines the type of NMII hexamer, defining three paralogs: NMII-A, NMII-B, and NMII-C. There is no definitive evidence of a selective binding of different RLC isoforms to the neck of the three heavy chain isoforms. This is not unexpected due to the almost complete sequence identity of the RLC isoforms.
Nonmuscle Myosin II, Fig. 1

Structure of the NMII hexamer. Top, image represents the two conformations of the NMII hexamer, 10S, which is assembly-incompetent, and the 6S, assembly-competent form. The 6S form is represented associated to a myosin filament and actin filaments (shaded). Bottom, color-coded nomenclature of the image

Regarding the coiled coil and nonhelical tail domain, these regions are thought to support the lateral interaction of the NMII hexamer with the equivalent region of other NMII hexamers to assemble antiparallel filaments (mini-filaments) that contain multiple hexamers (Ricketson et al. 2010), forming proto-sarcomeric structures in many cell types, particularly epithelial and mesenchymal cells. The size and stability of these mini-filaments depend of the isoform of the heavy chain. Although small filaments with a mixed composition have been described in cultured cells (Beach et al. 2014; Billington et al. 2015), many NMII filaments present in live cells contain only one type of hexamer. However, assemblies of different NMII isoforms can assemble along the same actin bundles, forming a characteristic stippled pattern observed by confocal and super-resolution microscopy (Vicente-Manzanares et al. 2007; Beach et al. 2014).

Mechanism of Filament Sliding and Force Generation

NMII-based actin filament sliding can be described in terms of the swing cross-bridge model (Spudich 2001). This model is shown in Fig. 2. Briefly, ATP-bound NMII is free, that is, not associated with the actin filament. When ATP is hydrolyzed by the Mg2+-actin-dependent ATPase activity of the head domain, NMII binds to the actin filament. The release of the resulting phosphate triggers a conformational movement that causes the sliding of the actin filament with respect to the NMII (10 nm/step on average). The exchange of ADP for ATP restarts the cycle. Mechanical work at a cellular level is caused by the concerted movement of many bundles of actin filaments propelled by multiple NMII filaments. A very important concept is the duty ratio, which can be defined as the fraction of time during which NMII remains bound strongly to actin in the ATPase cycle. The different isoforms display markedly different duty ratios (reviewed in Heissler and Manstein 2013). NMII-A displays the lowest duty ratio (0.05–0.1), which means NMII-A remains strongly bound to actin 5–10% of the time. This is similar to the duty ratio of muscle MII. Conversely, NMII-B has a much higher duty ratio (0.2–0.4), which likely represents an adaptation to bear tension, rather than to produce force. Finally, the duty ratio of NMII-C is splicing-dependent, but intermediate between NMII-A and NMII-B (Heissler and Manstein 2011). An interesting property is that the duty ratio of the NMII isoforms is load-dependent, which means that high load increases their duty ratio, particularly NMII-B (Kovacs et al. 2007). Duty ratio and the stability of NMII filament assemblies (see next section) are the two main properties that explain the different cellular functions of the isoforms.
Nonmuscle Myosin II, Fig. 2

The swinging cross-bridge model. Image depicts the cycle of NMII interaction with ATP and actin filaments. NMII in purple represents ATP-bound NMII (not bound to actin); light blue represents the intermediate ADP+Pi-bound state; and dark blue represents the actin-bound, ADP-containing state. The image also includes the exchange of ADP for ATP and release of the hydrolyzed phosphate. Note that for representation purposes, the cycle is represented as four symmetric stages, but the actual amount of time the NMII spends in one or another conformation is isoform-dependent (see text for details)

Two major regulatory checkpoints of NMII exist. One is the direct control of the actin binding/ATPase activity/ conformational movement of the NMII hexamer, which mainly takes place at the head and neck regions, including the RLC. The other is the control of the assembly state of the NMII hexamers (NMII filament growth/ disassembly equilibrium) as well as their subcellular localization. These two levels of control constitute the core of this review and are described in the following section.

Regulation of NMII Assembly and Activity

The major mechanism of regulation of the ATPase motor activity and filament assembly of NMII is through Ser/Thr phosphorylation. Several kinases have the potential to phosphorylate multiple sites in the RLC and the MHCII (Fig. 3). NMII serves as an endpoint of multiple signaling pathways that control NMII in different ways through the phosphorylation of various residues.
Nonmuscle Myosin II, Fig. 3

Regulation of the phosphorylation of the RLC (conformational extension and ATPase activity of the heavy chain) and of the heavy chain tail domain (filament assembly). Throughout the image, S indicates Ser residues and T denotes Thr residues, followed by their position in the corresponding RLC (left) or MHCII (right). Left, regulation of the RLC. Please refer to the text for details. CitK, citron-kinase; ROCK, RhO associated Coiled coil Kinase; MLCK, Myosin Light Chain Kinase; MYPT1, MYosin Phosphatase SubuniT1; MRCK, Myotonic dystrophy-Related Coiled-coil Kinase; PKC, protein kinase C; Ca2.CaM, calcium-calmodulin; GAP, GTPase Activating Protein; GEF, GTP Exchange Factor. Right, regulation of the NMII coiled coil and non-helical domain. Top right, tail of NMII-A. Bottom right, tail of NMII-B. CKII, casein kinase-II; TRPM6/7, Transient Receptor Potential Melastatin

RLC phosphorylation is the central regulatory event that controls NMII activity. The regulatory hotspot of the RLC is Ser19, which is responsible for the extension of the 10S NMII hexamer into the 6S assembly-competent form (Rosenfeld et al. 1994). It also promotes the activation of the motor ATPase activity of the NMII (Adelstein and Conti 1975). Additional phosphorylation at Thr18 further increases the actomyosin enzymatic activity and favors filament formation. In live cells, NMII phosphorylated in both Thr18 and Ser19 mainly appears in thick, stable actomyosin bundles, whereas NMII phosphorylated only in Ser19 is predominantly located in thinner, more dynamic filaments (Vicente-Manzanares and Horwitz 2010). Different kinases promote the phosphorylation of the RLC in Thr18 and Ser19. A major activating pathway emerges from the small Rho GTPase RhoA. When bound to GTP, RhoA binds to and activates ROCK (RhO-associated Coiled-coil Kinase). ROCK may phosphorylate RLC directly on Ser19 (Amano et al. 1996). However, the main function of ROCK in this context is the phosphorylation and inactivation of MYPT1, which is the catalytic subunit of a phosphatase specific for the RLC of NMII. In this manner, ROCK triggers NMII activation by promoting RLC phosphorylation directly and also by preventing its dephosphorylation. In addition, MYPT1 can be regulated in other ways, for example it can be phosphorylated and inhibited by ZIPK (Ichikawa et al. 1996). Also, the Arf GEFs Big1 and Big2 regulate its incorporation into complexes, thereby controlling its access to NMII (Le et al. 2013). CitK (citron kinase) is a RhoA-dependent cell cycle-related kinase that phosphorylates both Ser19 and Thr18 and controls the mitotic function of NMII (Yamashiro et al. 2003). Another Rho family member, Cdc42, activates MRCK (Myotonic dystrophy-Related Coiled-Coil Kinase), which also phosphorylates RLC on Thr18 and Ser19 (Leung et al. 1998). NMII is also directly regulated by calcium through the activation of the myosin light chain kinase (MLCK). This kinase is activated by Ca2+-calmodulin binding, and it phosphorylates RLC preferentially on Ser19 (Sellers et al. 1981). These kinases constitute a spatially segregated regulatory network, by which NMII is differentially activated throughout the cell. For example, MRCK and MLCK activate NMII closer to the leading edge (Totsukawa et al. 2004; Tan et al. 2008), whereas ROCK drives the activation of NMII in thick actomyosin bundles, which define the trailing edge of the cell (Totsukawa et al. 2004). Additional regulatory sites exist in the RLC, for example Ser1/Ser2. The phosphorylation of these Ser by PKC inhibits the function of NMII by decreasing the binding of NMII to actin filaments (Nishikawa et al. 1984; Komatsu and Ikebe 2007).

Regarding the control of NMII assembly into filaments, this is spatially mediated by the last loops of the α-helix coiled-coil rod domain and C-terminal nonhelical tail of the MHCII (∼last 200 amino acids of the MHCII). These regions interact laterally (mainly in an antiparallel fashion) with binding motifs in other NMII hexamers to mediate filament assembly. This interaction relies on intermolecular electrostatic interactions between negatively and positively charged regions that reside in this region of the MHCII. Importantly, this region contains most regulatory residues that underlie isoform specificity, thereby promoting homotypic interactions. This means that many mini-filaments contain only one type of paralog. Several kinases can regulate this activity, including TRPM (transient receptor potential melastatin)-6 and -7, members of the PKC (protein kinase C) family and CK2 (casein kinase 2). Regulation of these residues through phosphorylation introduces negative charges in selected regions of the different isoforms, which potentially destabilizes the electrostatic interactions between the chains and generally causes NMII disassembly and actomyosin filament instability that leads to cytoskeletal reorganization (Ricketson et al. 2010). TRPM7 also regulates NMII through the regulation of Mg2+ homeostasis (Stritt et al. 2016). These phosphorylations control the interaction of NMII with additional proteins. For example, NMII-A interacts with S100A4 (Mts1, metastatin-1) through a binding motif that comprises the last loops of the coiled-coil domain and the nonhelical tail domain. This interaction is regulated by phosphorylation of Ser1943 of NMII-A. Although this residue is not within the S100A4-NMIIA binding interface, its phosphorylation and the subsequent addition of negative charge may alter the conformation of the C-terminus of NMII-A, thereby preventing the interaction (Dulyaninova et al. 2005). Another interacting protein is Lgl (Lethal giant larvae), which is a tumor suppressor protein that binds to the C-terminal of both MHCII-A and -B under the control of aPKCζ and inhibits NMII-A assembly in live cells (Dahan et al. 2012). Myosin binding protein H (MYBPH) can directly interact with NMII to inhibit cell migration (Hosono et al. 2012). Additional regulators of NMII include various tropomyosin isoforms. Although muscle tropomyosin inhibits muscle myosin II binding to actin filaments, nonmuscle tropomyosin isoforms have variable effects on NMII function, depending on the tropomyosin and NMII isoform (Barua et al. 2014). Also, supervillin and anillin can bind NMII and control its function in cell division (Smith et al. 2013).

Pharmacological Control of NMII Function

A specific NMII inhibitor exists, blebbistatin (Straight et al. 2003). The (−) isomer of blebbistatin blocks the ATPase activity of NMII (Shu et al. 2005). In this manner, blebbistatin initially blocks contraction (the power stroke does not occur) and later detaches NMII from actin (Kovacs et al. 2004). Blebbistatin is not isoform-specific, and although its original form was phototoxic upon blue or UV light illumination (Kolega 2004), a recent derivative, para-nitroblebbistatin, is not (Kepiro et al. 2014). Pharmacological interventions are usually carried out at the regulatory level. For example, there are several specific inhibitors for ROCK, for example Y27632 and HA-1077 (fasudil) (Uehata et al. 1997). The latter is used in several countries to treat vasospasm, stroke, and cognitive decline in Alzheimer’s patients. There is an inhibitor for MLCK, ML-7. Inhibition of RhoA activity by ADP-ribosylation with C3 exoenzyme from Clostridium botulinum phenocopies many of the effects of direct NMII inhibition (Ridley and Hall 1992), but it has additional effects due to the role of RhoA as a controller of additional pathways involved in gene expression (Hill et al. 1995). Pharmacological activation of NMII can be elicited using a toxin produced by the Japanese sponge Discodermia calyx, calyculin A. This is a phosphatase inhibitor with moderate to low specificity for MYPT1 (Ishihara et al. 1989). On the other hand, no specific inhibitors of NMII assembly have been described yet. A recent study has identified a small molecule, 4-hydroxyacetophenone (4-HAP), which stabilizes NMII-B assemblies (Surcel et al. 2015), but the mechanism of such an effect remains unclear at present.

NMII-Dependent, Force-Sensitive Pathways

In addition to its position as a signaling endpoint, NMII activity also triggers many signal transduction pathways that contain mechano-reactive components, that is molecules that change their properties (binding, conformation, activity, etc.) in response to the application of mechanical force (Fig. 4a). This has been best illustrated in the case of cell-matrix adhesions. NMII activation generates mechanical work that increases the size of cell-matrix adhesions. This is due to several mechanisms occurring simultaneously. One is the lateral bundling of actin fibers, which brings diverse adhesion proteins into molecular proximity, triggering their interaction and thus increasing the number of molecules in cell-matrix adhesions (“clustering”). The other mechanism involves the conformational change of specific adaptors in response to mechanical work. One example is talin (TLN). When mechanically stretched, talin exposes a cryptic vinculin-binding site (del Rio et al. 2009), recruiting vinculin (and hence actin) to focal adhesions. Another example is p130CAS. This adaptor has a cryptic Tyr that is a substrate for Src only when p130CAS is stretched mechanically (Sawada et al. 2006). There is evidence of mechanically linked conformational or clustering changes to several components of cell-matrix adhesions, including integrins, zyxin (ZXN), and others (Yoshigi et al. 2005;Friedland et al. 2009) (shown in red in Fig. 4b). Cell-cell cadherin-based adhesions are also subject to mechanical regulation. For example, E-cadherin binds actin in a force-dependent manner through α-catenin (Buckley et al. 2014). In this manner, the forces generated by NMII are transmitted to cell-cell and cell-matrix adhesions, controlling their composition, interacting strength, and dynamics (Fig. 4c).
Nonmuscle Myosin II, Fig. 4

NMII is a signaling endpoint and an initiator of mechano-responsive signaling. (a) In red, the mechano-chemical regulation of NMII controls its conformation and actin binding and ATPase activity as well as its assembly into filaments of variable stability. In blue, the forces and work generated by the sliding of actin filaments driven by NMII promotes cytoskeletal remodeling, diverse effects on the molecular composition and stability of adhesive complexes (with other cells and the extracellular matrix) and even the modulation of gene expression by mechanical effects on the conformation of nuclear DNA. (b) Mechano-responsive cellular elements. The center of the image represents a cell that establishes cell-matrix adhesions (at the bottom) and cell-cell contacts (left and right, as indicated). Throughout the figure, NMII is represented in blue. Cell-matrix adhesive complex contain integrins (as indicated, in red/orange), TLN (talin), VCL (vinculin), PXL (paxillin), FAK (Focal Adhesion Kinase); CAS (p130CAS); ZXN (zyxin) and α-actinin (represented in pink as single anti-parallel arrays). Cell-cell adhesions contain cadherins (as indicated, in pink), vinculin and α- and β-catenin. The figure also depicts the nucleus enveloped in an actin-rich structure. In the nucleus, note the nesprin complex (nesprin/SUN/KASH), which connects the cytoskeleton and nucleoskeleton, and can transmit NMII-generated forces to chromatin through its interaction with nuclear lamins (sub-nuclear, dark blue). Molecules marked with an asterisk (*) change their conformation in response to force. Molecules in red have been shown to transmit forces through them independent of conformational changes. (c) The paths of the force. Figure is as in (b). Black arrows represent NMII-generated forces and how they are driven through actomyosin filaments to acting points, particularly cell-cell and cell-matrix adhesions, which control cell-cell interactions and matrix (ECM) remodelling, respectively. Forces are also transmitted to the nucleus, driving mechanically-regulated chromatin extension

Mechanical regulation of gene expression is another point of great interest. Several transcription factors are activated in response to NMII-dependent mechanical signals, for example Yap/Taz or Nkx2.5 (Piccolo et al. 2014; Dingal et al. 2015). The precise mechanism of activation is still unclear, but it requires the translocation of the transcription factor from the cytoplasm to the nucleus, which is promoted by NMII-dependent forces. It also requires the binding of the transcription factor to its DNA targets in the nucleus, which depends on the degree of chromatin extension. Chromatin extension could be controlled by NMII-dependent forces through the connection of the cytoplasmic cytoskeleton to the nucleoskeleton through nuclear nesprin/SUN/KASH complexes (Fig. 4b, c). The connection of nucleoskeleton proteins to chromatin suggests that these forces may expose loops of condensed chromatin DNA, which would become accessible to mechano-sensitive transcription factors, enabling the expression of specific genes in response to mechanical cues. This is how stiff environments are thought to promote stem cell differentiation into osteoblasts: a stiff substrate would activate NMII, which would transmit mechanical forces to chromatin through nuclear complexes, exposing DNA binding sites related to genes involved in osteogenesis. Although the mechanisms that control transcription factor shuttling in and out of the nucleus in response to mechanical forces are still unclear, some mediators have been identified in specific cell types, for example E-cadherin/β-catenin in epithelia (Benham-Pyle et al. 2015).

Mechanically driven gene expression is clearly an area of rapid development that aims to define the mechano-responsive elements in the nucleus that drive chromatin exposure under different mechanical stimuli. It is interesting to note that some of the mechano-responsive transcription factors identified so far, for example Yap/Taz and Nkx2.5, are also implicated in morphogenetic pathways that control the growth of tissues to their proper size. This suggests that the relationship between the shape of individual cells and tissues as a whole is conjoined by the convergence of mechanical signals and genetic responses.

Myh9/Myh14 Syndromes

Several genetic diseases are associated to mutations to the human Myh9 gene (Seri et al. 2000). These include the May-Hegglin anomaly and Epstein, Fechtner, and Sebastian syndromes, which are now collective referred as Myh9-related diseases. Mutations affect different domains of the molecule (Fig. 5); hence, they compromise different aspects of NMII-A function, from ATPase activity (mutations to exons 2–20) to dimerization (exons 21–39) to mini-filament assembly (exon 40). These syndromes have several specific clinical manifestations, which accumulate over time. The most common clinical manifestation of these syndromes is macrothrombocytopenia, which is a shortage of mature platelets and the appearance of giant platelets in the bloodstream (Althaus and Greinacher 2009). Other manifestations include Döhle-like neutrophil inclusions, deafness, nephropathy, and cataracts. Döhle-like inclusions are likely aggregates of protein that cannot form filaments, and they appear in all of these syndromes except Epstein’s. The etiology of the other alterations is less clear, but it seems related to mechanical compromise and/or impaired renewal of cells that control mechanically active processes, for example sound transmission in the ear (deafness), glomerular filtration in the nephrons (nephropathy due to glomerulosclerosis), or light transmission in the eye (cataracts). Interestingly, mutations in the head and rod domain of mouse Myh9 gene cause similar defects to those observed in Myh9 patients (Zhang et al. 2012).
Nonmuscle Myosin II, Fig. 5

Some Myh9-specific mutations cause disease in humans. Panel includes mutations to the head domain (in green), the coiled-coil domain (in blue) and the single mutation ascribed to the junction between the non-helical and coiled-coil domain (in red). The Table embedded in the figure describes the DNA mutations with its corresponding exon and the result of the mutation in terms of protein sequence

A mutation in the gene Myh10 has been recently identified, with a phenotype consisting of intrauterine growth restriction, microcephaly, developmental delay, failure to thrive, congenital bilateral hip dysplasia, cerebral and cerebellar atrophy, hydrocephalus, and congenital diaphragmatic hernia (CDH) (Tuzovic et al. 2013). This mutation phenocopies some aspects of mice strains carrying loss-of-function mutations to this gene (Ma et al. 2004). Finally, autosomal dominant hearing impairment (DFNA4) is associated to a mutation in Myh14. Myh14 encodes the heavy chain isoform II-C. This isoform is expressed in the cochlea and several mutations are associated to DFNA4, including 20c>a = S7X (stop mutation in the motor domain); 1126 g>t = G376C and 2176c>a = R726S (both in the motor domain); and 2926c>t = L976F (in the coiled-coil domain) (Donaudy et al. 2004).


Nonmuscle myosin II has emerged as a central protein at the interface between chemistry and physics in terms of the control of the cellular behavior. This is mainly due to its ability to generate mechanical force and actin filament work, as well as its actin cross-linking properties. Two major mechanisms of control exist, related to the actin-binding and ATPase activity of the molecule as well as the stability of the NMII subunits in filaments. In addition to the human syndromes associated to single-site mutations in the MHCII, NMII plays central roles in cancer and inflammation as it controls cancer cell division, the physical integrity of tumor masses, their dissemination, and their implantation at distant sites from the original tumor. It also determines the mechanical properties of the extracellular microenvironment, which may promote, or inhibit, the development of these diseases. Finally, NMII also participates in leukocyte proliferation and migration, that is, the systemic response of multicellular organisms against external aggression or anomalous growth. Although too central to be a useful pharmacological target to treat disease so far, its complex regulation together with its ubiquity in terms of cellular function and tissue expression makes NMII a crucial mediator of most cellular responses and a lynchpin of the biology of complex organisms.



We regret the large number of original articles that were left out due to space constraints. Dr. Vicente-Manzanares would like to thank Prof. Robert S. Adelstein, Dr. Mary Anne Conti and Dr. Xuefei Ma for critical reading of the manuscript and their advice, help and warm friendship over the years. This work was funded by grant SAF2014-54705-R from MINECO. Miguel Vicente-Manzanares is a Ramon y Cajal Assistant Professor (RYC2010-06094).


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Alba Juanes-García
    • 1
  • Clara Llorente-González
    • 1
    • 2
  • Miguel Vicente-Manzanares
    • 1
    • 2
  1. 1.Department of Medicine, Universidad Autonoma de Madrid School of MedicineU.D. Hospital Universitario de la PrincesaMadridSpain
  2. 2.Instituto de Biología Molecular y Celular del Cáncer-CSICSalamancaSpain