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(Circulation Research. 2000;87:173.)
© 2000 American Heart Association, Inc.

Editorials

Myosin Light Chain Phosphatase

A Cinderella of Cellular Signaling

R. John Solaro

From the Program in Cardiovascular Sciences, Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Ill.

Correspondence to R. John Solaro, PhD, Department of Physiology and Biophysics (M/C 901), College of Medicine, University of Illinois at Chicago, 835 S Wolcott Ave, Chicago, IL 60612-7342.

Key Words: small G proteins • myosin light chain • phosphatase • vasospasm • stroke

	Introduction

Top Introduction Modulation of MLCP During... A Rich Array of... Broad Implications of Regulation... References

 
Although several myofilament proteins are modified by protein phosphorylation, the 18-kDa myosin light chain 2 (MLC2) has special significance. In striated muscle, after some experimental struggles, MLC2 phosphorylation was shown to modulate myofilament activation by Ca²⁺.¹ However, in the case of smooth muscle, phosphorylation of the MLC2 by a Ca²⁺ calmodulin–dependent kinase triggers contraction.² The state of MLC2 phosphorylation in smooth muscle determines whether crossbridges are turned off, cycling, or in a latch or catch-like state. Understandably, the initial focus of experiments was on Ca²⁺ and the regulation of MLC2 kinase (MLCK) activity. It was always understood that control of the level of MLC phosphorylation requires some balance of activities and separation of powers between an MLCK and MLC2 phosphatase (MLCP),³ yet little attention was given to the possibility that the activity of MLCP could be modulated. Now MLCP seems to be the Cinderella of phosphoryl group transfer enzymes.

This mindset concerning regulation of MLC2 phosphorylation changed dramatically with two observations. One was evidence that addition of GTP--S to permeable preparations of smooth muscle was able to sensitize the myofilaments to Ca²⁺ and slow down relaxation, alterations suggesting modulation of MLCP.⁴ A second was the elucidation of the functional domains of MLCP,⁵ which consist of a 37-kDa catalytic subunit, a 20-kDa subunit of unknown function, and a 110- to 130-kDa subunit that targets MLCP to myosin. This targeting domain of MLCP, which is termed myosin binding site (MBS) or myosin phosphatase targeting peptide, binds to myosin or MLC2 and promotes catalytic activity of the 37-kDa domain. MBS was also shown to contain Ser and Thr residues, which, when phosphorylated, inhibit the ability of MBS to activate the catalytic domain, thereby reducing activity of the MLCP holoenzyme.⁵ A significant pathway for modulation of MLCP activity is by a signaling cascade involving the small G protein Rho and its activation of Rho-kinase, which phosphorylates MBS.^{6 7 8}

	Modulation of MLCP During Physiological and Pathological Conditions

Top Introduction Modulation of MLCP During... A Rich Array of... Broad Implications of Regulation... References

 
In this issue of Circulation Research, Sato et al⁹ provide compelling evidence that an increase in MLCP activity is a significant mechanism for inducing vasospasm after simulated subarachnoid hemorrhage in a dog model. Most evidence suggesting that various pathways may modulate MLCP activity has come from in vitro observations either in cell-free systems or permeable cells under nonphysiological conditions. It is apparent that much work needs to be done to define the physiological significance of this mechanism and how it may be modified in pathological conditions. The study by Sato et al⁹ provides an important piece of this puzzle. An attractive feature was the use of an in situ cerebral artery chronically stressed by hemorrhage with an experimental readout of function, MLCP activity, Rho-kinase activation, and MLC2 phosphorylation determined over time after the insult. Measuring the changes that occurred with time permitted correlations between vasospasm, MLC2 phosphorylation, Rho-kinase activation, and MBS phosphorylation. It was important that the study did not rely on the use of ³²P, which often is applied to cells in extraordinarily high specific activity leading to a potential for artifacts. Also important was the availability and use of Y27632, a specific inhibitor of Rho-kinase.^{10 11} The correlations that were reported by Sato et al⁹ support their conclusion. Thus, in addition to and possibly independently of elevated Ca²⁺ and an associated µ-calpain and MLCK activation, inhibition of MLCP through the RhoA–Rho-kinase pathway contributed significantly to the vasospasm. The data provided by Sato et al⁹ suggest a substantial in situ separation of powers in the kinase and phosphatase activities and indicate that physiological homeostatic mechanisms are likely to use tight but separate control of both kinase and phosphatase activities through feedback control mechanisms that are poorly understood. Understanding these mechanisms in the integrated biology of smooth muscle remains an important challenge.

	A Rich Array of Second Messenger Cascades Potentially Modulates MLCP Activity

Top Introduction Modulation of MLCP During... A Rich Array of... Broad Implications of Regulation... References

 
The study by Sato et al⁹ raises important questions of how the RhoA–Rho-kinase pathway is activated after the insult of hemorrhage, how MLCP activity is regulated in general, and whether these mechanisms are altered in various pathological states. MLCP is affected not only by various signaling cascades that might alter the state of phosphorylation of MBS, but there are also multiple sites for regulation by protein factors that could modify the interactions among the subunit domains involved in MLCP targeting and catalysis. There is evidence for modulation of MLCP activity by either activator or repressor proteins, whose activity is modified by phosphorylation. A potential activator protein is telokin, which comprises an independently expressed C-terminal domain of MLCK.^{12 13} It is not clear whether telokin acts by modifying the activity of MLCP directly or indirectly by interactions with MLC. Whatever the case, its activity as a promoter of MLCP activity is amplified when telokin is phosphorylated by activation of the protein kinase A (PKA) and PKG pathways in vitro and in situ in permeabilized cells. Correlation of telokin abundance with activity suggests physiological significance for this mechanism. For example, telokin is expressed to a greater extent in phasic than in tonic smooth muscles.⁸ CPI17 is a potential repressor protein in the regulation of MLCP, which may be important in the inhibition of smooth muscle contraction by PKC.^{14 15} It is a substrate for PKC, and, when phosphorylated, CPI17-induced inhibition of MLCP is potentiated.¹⁵ Another modulator of MLCP is arachidonic acid (AA), which is released by the phospholipase A₂. AA may block the interaction of the MBS peptide with its substrate or alternatively activate a kinase that phosphorylates the MBS.^{8 16} Taken together, these data indicate clearly the multiple diverse pathways by which MLCP activity may be modified. It seems likely that the actions of agonists affecting smooth muscle contraction could work by affecting the activity of AA, telokin, and CPI17 through the G protein–coupled receptor cascades promoting the activity of PKC, PKA, and PKG.

As emphasized by Sato et al,⁹ small G proteins, especially RhoA, also seem likely to inhibit MLCP in a mechanism that increases Ca²⁺ sensitivity of the contractile apparatus. After the observation^{4 8} that addition of GTP--S to permeabilized smooth muscle preparations sensitized force to Ca²⁺, RhoA was identified as most likely to activate the affected GTP binding protein. The involvement of RhoA in this effect was inferred from studies demonstrating that botulinum exotoxin, which specifically ADP-ribosylates and inactivates the Rho family, completely abolished the sensitizing effect of GTP--S.⁶ A major step in understanding how RhoA might affect MLCP and dephosphorylate MLC came with the report⁷ that RhoA induces activation of a dependent kinase (RhoA-kinase), which, in turn, phosphorylates MBS, thereby blunting the activity of the phosphatase. There is also in vitro evidence that RhoA kinase may directly phosphorylate the MLC2.¹⁷ Sato et al⁹ suggest this as a possible partial explanation for their demonstrated increase in MLC2 phosphorylation in cerebral vessels after hemorrhage. However, direct phosphorylation of MLC2 by Rho-kinase seems unlikely inasmuch as it has been shown that activation of Rho-kinase has no effect on force of permeable smooth muscle in the absence of Ca²⁺ when there is no MLC phosphorylation.¹⁸

Regulation upstream of Rho-kinase occurs at the level of RhoA. The activity of Rho-kinase is dependent on Rho GDP and GTP exchange, which is in turn regulated by guanine nucleotide exchange factors (GEF).¹⁹ GEF-RhoA directly connects RhoA activity to the subunit of G proteins in the signal transduction through receptors such as the ß-adrenergic and thromboxane receptors.⁸ RhoA is also regulated by Rnd1, a new member of the Rho family.²⁰ Rnd1 is constitutively bound to GTP and able to block Ca²⁺ sensitization by RhoA. Interestingly, expression of Rnd1 was greatly enhanced in aorta and intestinal smooth muscle from rats treated with estrogen. Sauzeau et al²¹ recently reported a direct phosphorylation of RhoA by cGMP-dependent protein kinase (cGK). cGK phosphorylation inhibited the ability of RhoA to induce Ca²⁺ sensitization of permeable smooth muscle preparations. This observation connects RhoA and Rho-kinase to the vasodilatory effects of NO and nitroprusside.

	Broad Implications of Regulation of MLCP

Top Introduction Modulation of MLCP During... A Rich Array of... Broad Implications of Regulation... References

 
The study by Sato et al⁹ has broad implications. Smooth and nonmuscle myosin motors (myosin II) regulate diverse cellular processes, and regulation of MLCP by the RhoA–Rho-kinase pathway as well as other pathways may have broad biological significance in normal and pathological conditions. In the case of smooth muscle, regulation of blood pressure, intestinal motility, and airway resistance are likely to be regulated by MLCP in the physiological state and may be modified in hypertension and asthma.⁸ There is strong evidence that Rho-kinase may induce regional hypercontractility in coronary vasospasm. Kandabashi et al²² reported that the spastic site exhibited an increase in Rho-kinase RNA and an associated increase in MBS phosphorylation that could be inhibited by Y27632. A role for the Rho–Rho-kinase pathway in atherogenesis associated with pathological platelet activation has been proposed.²³ Moreover, Rho-kinase has also been proposed to play a key role in restenosis, neointimal formation, and growth after balloon injury.²⁴ Along these lines, Yamakawa et al²⁵ reported that angiotensin II, which has been implicated in hypertrophy and hyperplasia of smooth muscle cells, induced a translocation of RhoA from membrane to particulate fraction and that blockers of Rho-kinase blocked smooth muscle protein synthesis. Therefore, modulation of MLCP by Rho-kinase MLCP may be important in a variety of vascular smooth muscle disorders, including hypertension, vasospasm, atherogenesis, and proliferative disorders.

Effects of Rho-kinase on cell proliferation are not limited to smooth muscle.²⁶ For example, Rho-kinase activity may be of general significance in processes related to tumor development, invasion, and metastasis. Modulation of the epithelial-mesenchymal transition, dispersal of epithelial cells, and formation of focal adhesions and stress fibers seems to involve opposing roles of p21-activated kinase and Rho-kinase. Interestingly, p21-activated kinase has been shown to phosphorylate MLCK and decrease its activity.²⁷ Rho-kinase would be expected to have the opposite effect. Somlyo et al²⁸ also reported evidence suggesting that the Rho–Rho-kinase pathway facilitated invasive progress of prostate cancer. As in the results reported by Sato et al,⁹ it is apparent that both activation of MLCK and inhibition of MLCP may be acting to promote invasion and metastasis of malignant cells.

Central nervous system effects of Rho-kinase in neuronal development and growth may also be related to its modulation of MLCP.²⁹ The most extensive progress in this area has been in cytoskeletal biology, where a link has been established between GTPases and the assembly of filamentous actin. For example, a recent study by Arimura et al³⁰ demonstrated the existence of Rho-kinase–dependent pathways that determine the state of the growth cone of the developing neurite. How this happens remains unclear, but it seems likely that a combined action of kinases and phosphatases are part of the mechanism. Adducin, an actin-binding phosphoprotein that signals focal adhesion, has been demonstrated by Kimura et al³¹ to be directly phosphorylated by Rho-kinase. In a process parallel to that occurring with MLCP, Kimura et al³¹ also reported that Rho-kinase phosphorylation of MBS inhibited dephosphorylation of adducin. These results clearly indicate the potential for a general mechanism that determines the state of phosphorylation of diverse proteins and that MBS on MLC interacts with effectors other than MLC2.

The number of cellular signaling pathways that we know are switched on and off or modified by protein phosphorylation is vast and certain to increase with modern high-throughput approaches. RhoA itself had over 30 effectors at last count.²⁹ A general principle, clearly supported by the findings of Sato et al,⁹ is that the complexity of the signaling cascades that activate and modify kinases is matched in the case of regulation of the phosphatases. Importantly, inhibition of phosphatases is a realistic therapeutic target in the control of diverse clinical conditions such as hypertension, asthma, restenosis, metastasis of tumor cells, and, no doubt, others. It will be exciting to see if the glass slipper of a therapeutically useful agent fits this Cinderella of enzymes involved in phosphoryl group transfer.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction Modulation of MLCP During... A Rich Array of... Broad Implications of Regulation... References

 

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Solaro, R. J. Search for Related Content PubMed PubMed Citation Articles by Solaro, R. J. Related Collections Other Vascular biology Animal models of human disease Cerebral Aneurysm, AVM, & Subarachnoid hemorrhage