© 2000 American Heart Association, Inc.
Editorials |
Myosin Light Chain Phosphatase
A Cinderella of Cellular Signaling
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
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Introduction |
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 Top Introduction Modulation of MLCP During...A Rich Array of...Broad Implications of Regulation...References |
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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
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Modulation of MLCP During Physiological and Pathological Conditions |
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TopIntroductionModulation of MLCP During...A Rich Array of...Broad Implications of Regulation...References |
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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.
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A Rich Array of Second Messenger Cascades Potentially Modulates MLCP Activity |
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TopIntroductionModulation of MLCP During...A Rich Array of...Broad Implications of Regulation...References |
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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 observation4 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.
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Broad Implications of Regulation of MLCP |
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TopIntroductionModulation of MLCP During...A Rich Array of...Broad Implications of Regulation...References |
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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.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionModulation of MLCP During...A Rich Array of...Broad Implications of Regulation...References |
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