From the Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040
Cell signaling events that lead to increased
[Ca2+]i1
in smooth and skeletal muscles activate
Ca2+/calmodulin-dependent MLCK. The kinase
phosphorylates a specific site on the N terminus of the RLC of the
molecular motor myosin II (1-3). RLC phosphorylation is sufficient to
initiate contraction in smooth muscle, but in striated muscles, RLC
phosphorylation potentiates the force and speed of contractions that
are dependent on Ca2+ binding to troponin on
actin-containing thin filaments. The only known physiological substrate
for MLCK is myosin RLC; thus, it is a dedicated protein kinase.
Interest in RLC phosphorylation has increased substantially with recent
reports implicating phosphorylation-dependent myosin II
activity in many functions of nonmuscle cells. These include cell
spreading and migration, neurite growth cone advancement, cytokinesis,
cytoskeletal clustering of integrins at focal adhesions, stress fiber
formation, platelet shape changes, secretion, transepithelial permeability, and cytoskeletal arrangements that affect ion currents or
exchange at the plasma membrane (4-8). The potential importance of RLC
phosphorylation in pathophysiological processes involving cell
migration is apparent, but less obvious involvements may include
cerebral vasospasm (9), increased endothelial permeability during
inflammation (10), and asthma (11).
In vertebrates there are two genes for MLCK (3). The skeletal
muscle MLCK gene encodes a kinase catalytic core and regulatory segment
containing autoinhibitory and Ca2+/calmodulin-binding
sequences (Fig. 1).
INTRODUCTION
TOP
INTRODUCTION
Myosin Light Chain Kinase...
Activation by Ca2+/Calmodulin
Phosphorylation of Smooth...
Some Biological Functions of...
Concluding Remarks
REFERENCES
Myosin Light Chain Kinase Family
TOP
INTRODUCTION
Myosin Light Chain Kinase...
Activation by Ca2+/Calmodulin
Phosphorylation of Smooth...
Some Biological Functions of...
Concluding Remarks
REFERENCES
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Fig. 1.
A schematic of structural and functional
elements in myosin light chain kinase and related protein
kinases.
The smooth muscle MLCK gene expresses three transcripts in a
cell-specific manner due to alternate promoters (12-14). Smooth muscle
tissues normally have a short form of the kinase containing a catalytic
core and regulatory segment that differ in sequence and catalytic
specificity from skeletal muscle MLCK (Fig. 1). This kinase also
contains three Ig modules, one Fn module as well as a PEVK repeat-rich
region and an actin-binding sequence at the N terminus (Fig. 1). The Ig
and Fn modules have sandwich structures whereas the PEVK module is
responsible for the titin-dependent elastic properties of
striated muscle sarcomeres (15). The functions of these sequences in
MLCK are not clear. However, the actin-binding sequence is both
necessary and sufficient for high affinity binding in vitro
and in vivo (16, 17). Although it was proposed that the
actin-binding sequence resides in amino acids 1-41 of the short
isoform (17), more recent evidence demonstrates the importance of three
repeat motifs (DFRXXL) in residues 2-63, each of which may
bind a single actin monomer in an actin filament (18, 19). Thus, the N
terminus of MLCK may be anchored to actin thin filaments with extension
of the catalytic core to myosin thick filaments for RLC
phosphorylation. Smooth muscle MLCK is ubiquitous in all adult tissues
with the highest amounts in smooth muscle tissues whereas the skeletal
muscle kinase is tissue-specific (20).
Another transcript of the smooth muscle MLCK gene results in a longer form of the kinase. It contains all of the shorter MLCK in addition to an N-terminal extension with six Ig modules and two additional actin-binding motifs in tandem (Fig. 1). The N-terminal extension may be responsible for an increased affinity for actin-containing filaments (21). This kinase is not normally expressed in adult smooth muscle tissues but is found in smooth muscle cells in culture, in embryonic smooth muscle tissue, and in nonmuscle cells (12, 22, 23). The longer smooth muscle MLCK has been referred to as embryonic, nonmuscle, endothelial cell or the 210-kDa MLCK. However, the short form is also expressed in smooth muscle during embryogenesis and in some nonmuscle cells; moreover, the long form is not restricted to endothelial cells and is variable in size (20 kDa) in different animal species because of the number of PEVK repeat sequences (3, 12, 22-24). We thus propose a simplified terminology of long and short smooth muscle MLCK, which could also accommodate recently reported alternatively spliced transcripts (80).
The third transcript of the smooth muscle MLCK gene is the C-terminal Ig module, which results in the expression of the telokin protein in phasic smooth muscle tissues (14). Telokin may contribute to Ca2+ desensitization of smooth muscle force by cyclic nucleotides (25).
Other kinases are related to the MLCK family (15). Titin, a molecular template for sarcomere assembly and passive elasticity in vertebrate striated muscles, contains a single kinase domain (26). The 3.0-mDa titin polypeptide contains 132 Fn and 166 Ig modules (Fig. 1). The titin kinase has a two-step activation mechanism involving tyrosine phosphorylation in the active site followed by Ca2+/calmodulin binding (26), leading to phosphorylation of telethonin, a Z-disc protein required for sarcomere formation.
Kinases related to vertebrate skeletal and smooth muscle MLCKs are also
found in invertebrates. A single Drosophila gene produces from multiple internal promoters a number of transcripts with overlapping ends (15). Small transcripts (3.2-5.2 kb) encode kinase
proteins similar in size to the vertebrate MLCKs whereas larger
transcripts (13-25 kb) encode giant proteins similar to mammalian
titins. The largest 25-kb transcript encodes a 926-kDa stretchin MLCK
that has multiple structural modules (Fig. 1). Caenorhabditis elegans and Aplysia
express the related kinase, twitchin. The crystal structure of the
catalytic region of twitchin kinase shows an autoinhibitory segment
binding to the catalytic core. It does not contain a classical
calmodulin-binding sequence, but it is activated by the
Ca2+-binding protein, S100A12 (27). The
Dictyostelium MLCK is structurally the simplest related
kinase containing a catalytic core and a regulatory segment that must
be phosphorylated for activation (Fig. 1) (28).
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Activation by Ca2+/Calmodulin |
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Upon complex formation with a calmodulin-binding peptide derived
from MLCK, Ca2+/calmodulin undergoes a conformational
collapse with its two domains wrapping around the peptide through the
bending of a flexible central helix (29-31). The calmodulin-binding
sequences of both smooth and skeletal muscle MLCKs then form an
amphiphilic -helix.
Kinetic and equilibrium studies of the binding interactions among Ca2+, calmodulin, and MLCK, as well as small-angle x-ray and neutron scattering results are consistent with an ordered sequence of events culminating in MLCK activation (3, 24, 32-37). The autoinhibitory sequence folds back on the surface of the large lobe of the MLCK catalytic core and prevents RLC but not ATP binding in the catalytic cleft. Results from protein fragmentation complementation analyses indicate that the principal autoinhibitory motif is contained within the sequence between the catalytic core and the calmodulin-binding sequence (36) consistent with previous results obtained with truncation mutants (38). Residues C-terminal to the calmodulin-binding sequence (including the Ig module) are not functional components of the regulatory segment (36).
In the presence of Ca2+, the C-terminal domain of
calmodulin binds to the N terminus of the calmodulin-binding sequence
in MLCK with the subsequent binding of the N-terminal domain to the C terminus of the calmodulin-binding sequence (Fig.
2). Ensuing calmodulin interactions with
the catalytic core per se appear to be necessary for
activation (3, 33, 39, 40). Although calmodulin binding and activation
processes are basically similar for smooth and skeletal muscle MLCKs,
mutated calmodulins with abilities to activate one or the other kinase
indicated distinct differences in target-specific interactions (33,
41). The regulatory segment is subsequently displaced from the
catalytic site with calmodulin collapsed at a position near the end but adjacent to the catalytic core (Fig. 2). The exposed catalytic site of
the kinase allows the N terminus of RLC to bind with closure of the
cleft and transfer of phosphate from ATP to RLC resulting in the
reorientation of calmodulin.
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Phosphorylation of Smooth Muscle MLCK in Vitro |
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The activity of smooth muscle MLCK can be modulated by
phosphorylation at specific sites that lead to increased
KCaM or Vmax values (Fig.
3); however, both nonphosphorylated and
phosphorylated MLCKs are tightly regulated by
Ca2+/calmodulin binding, and no evidence exists for
physiologically relevant Ca2+/calmodulin-independent
activity. The most well documented effect of MLCK phosphorylation is a
10-fold increase in KCaM that occurs upon
phosphorylation of one of two serine residues in the C terminus of the
calmodulin-binding sequence. Several protein kinases phosphorylate this
site in vitro, including protein kinase A (42), protein kinase C (43), CaMK II (44), and PAK (45). MLCK contains several
phosphorylation consensus sites for proline-directed protein kinases,
and phosphorylation of either of two sites outside of the catalytic
core and regulatory segment by members of the MAPK family increases
Vmax with no change in
KCaM (46, 47).
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Some Biological Functions of Smooth Muscle MLCKs |
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Because of its dedicated nature, MLCK figures prominently in efforts to define the regulation of actomyosin-dependent functions in both smooth and nonmuscle cells where all isoforms of myosin II are activated by RLC phosphorylation (2, 5). The extent of RLC phosphorylation represents a balance between the relative activities of MLCK and myosin phosphatase, both of which are subject to extensive regulation (Fig. 3).
Smooth Muscle-- In both intact and permeable smooth muscle fibers, increases in [Ca2+]i result in increased RLC phosphorylation and force (1, 2). The sufficiency of RLC phosphorylation for contraction is shown by treatment of both intact cells and skinned fibers with proteolytically activated MLCK in the absence of elevated [Ca2+]i (2). The dependence of force on steady state RLC phosphorylation is described by a unique relation for most contractile and dilatory agents, with a few exceptions that may point to thin filament-linked or other collateral types of regulation (48). The dependence of RLC phosphorylation on [Ca2+]i in differentiated smooth muscle arises from the Ca2+/calmodulin-dependent activity of short MLCK bound to myofilaments (49).
The sensitivity of RLC phosphorylation to [Ca2+]i can be modulated by the action of different signaling pathways that modify MLCK or myosin phosphatase activities (Fig. 3). Ca2+ sensitization of RLC phosphorylation is observed where [Ca2+]i remains constant and RLC phosphorylation increases in response to application of agonists that lead to GTP-dependent inhibition of myosin phosphatase (50). Smooth muscle myosin phosphatase is a type 1 serine/threonine phosphatase consisting of a 110-130-kDa myosin-binding subunit, a 37-kDa catalytic subunit (PP1c), and a 20-kDa subunit with unknown function. Inhibition is effected by changes in subunit interactions occurring in response to phosphorylation of the myosin-binding subunit by Rho kinase (51) or other unidentified kinases (52). Inhibition can also be brought about by the action of CPI-17 when phosphorylated by protein kinase C (53).
Ca2+ desensitization of RLC phosphorylation occurs upon
phosphorylation of MLCK at the C terminus of the calmodulin-binding sequence and subsequent increase in KCaM.
Although the predominant response of smooth muscles to dilatory agents
such as -adrenergic agonists or nitric oxide is diminished
[Ca2+]i, inhibition of RLC phosphorylation can be
brought about without reductions in [Ca2+]i such
as when cAMP is elevated in depolarized muscles (54). In this case,
phosphorylation of MLCK is increased but not in the site that increases
KCaM (55, 56), suggesting that Ca2+
desensitization of RLC phosphorylation may result from the
cAMP-dependent activation of myosin phosphatase (25, 54,
55). Surprisingly, MLCK is phosphorylated on the C terminus of the
calmodulin-binding sequence in a Ca2+-dependent
manner during smooth muscle contractions by CaMK II, resulting in
desensitization of RLC phosphorylation to [Ca2+]i
(49, 55, 56). Although recent pharmacological studies with inhibitors
of CaMK II proposed MLCK phosphorylation did not contribute to
desensitization (57, 58), the observed decreases in force and RLC
phosphorylation likely arose from inhibition of CaMK II activity on
Ca2+ channels resulting in decreased
[Ca2+]i (59, 60). [Ca2+]i
thus acts in two ways to regulate
Ca2+-dependent RLC phosphorylation; it acts
positively to increase RLC phosphorylation by activating MLCK, and at
greater concentrations it acts negatively on RLC phosphorylation by
stimulating CaMK II phosphorylation of MLCK. MLCK is likely to be
dephosphorylated in vivo by myosin phosphatase as its
phosphorylation is potentiated by agents known to inhibit myosin
phosphatase such as agonists and GTP
S (61). This may represent
feedback inhibition of the Rho-kinase-mediated Ca2+
sensitization pathway.
Nonmuscle Cells-- Phosphorylated myosin II is an important effector of cytoskeletal activities in a number of cellular functions (Fig. 3). Many of these functions arise in response to extracellular signals that dictate temporally and spatially coordinate increases in [Ca2+]i and rearrangements of the actin cytoskeleton (62). Ca2+-independent cell signaling pathways also regulate target effectors including a host of actin-binding proteins and the motor protein myosin II (4, 63). These pathways generally couple ligand-bound receptors to the cytoskeleton through activation of small GTP-binding proteins including Cdc42 and Rac with effector kinases, PAK and MEK kinase, and Rho with its effector kinase, Rho kinase (64). There is growing interest in the role of MLCK in regulating myosin II ATPase activity during various motile processes and modulation by these Ca2+-independent signaling pathways. Some examples of these current topics follow.
Myosin II is regulated by the Ca2+/calmodulin-dependent MLCK with the necessary kinetic properties that dictate the rate and direction of cell movement in response to temporally and spatially complex extracellular signals. Photolysis of caged inhibitory peptides directed to either calmodulin or MLCK results in blockade of cell locomotion, granule flow, and forward motion of the leading lamellipod within a few seconds in motile, polarized eosinophils (65). However, the formation of phase dark ruffles and lamellar extensions, processes believed to be dependent on actin polymerization, continues. In the smooth muscle cell line SM3, decrease of MLCK by antisense mRNA inhibited both motility and lamellipodia formation (66). Motility in eosinophils and fibroblasts is associated with elevated [Ca2+]i, and Ca2+/calmodulin-dependent MLCK appears to be a major molecular control mechanism for cell locomotion (65). However, these conclusions cannot be generalized to all locomoting cells as polarization and chemotaxis occur in some cell types without changes in [Ca2+]i (62).
Short and long isoforms of smooth muscle MLCK may have distinct cellular functions. Fluorescence imaging of green fluorescent protein-tagged long MLCK showed this isoform to be localized to the cleavage furrow of dividing HeLa cells, whereas the green fluorescent protein-tagged short form was diffusely distributed in the cytoplasm (67). Localization to the cleavage furrow required the five actin-binding motifs and the N-terminal extension, whereas localization of long or short MLCK to actin filaments during interphase required only the actin-binding motifs.
MLCK activity may be modulated by signaling pathways known to regulate cytoskeletal morphology. Phosphorylation of MLCK with an associated decrease in RLC phosphorylation and disassembly of stress fibers was observed in fibroblasts injected with cAMP-dependent protein kinase (68). These results are consistent with the well documented role of myosin II activity in stress fiber assembly (69) and also with cAMP-mediated desensitization of MLCK (Fig. 3). Nevertheless, some caution is warranted because of the findings that activation of the cAMP pathway in smooth muscle did not increase KCaM (1, 3).
MLCK is also a target of the Rho family of GTPases in signaling to the cytoskeleton (45, 70-72). MLCK phosphorylation by PAK is associated with decreased MLCK activity, inhibition of RLC phosphorylation, and inhibition of cell spreading or contraction (45, 70). PAK is strongly implicated in cell locomotion, and other studies have shown that constitutively activated PAK can induce motility/contractility and RLC phosphorylation, potentially through its ability to phosphorylate myosin RLC directly (71-73). The RhoA pathway leads to stress fiber assembly and focal adhesion formation by inhibiting myosin phosphatase activity and thereby enhancing RLC phosphorylation (4, 63). Interestingly, Rho kinase may directly phosphorylate myosin RLC in stress fibers whereas MLCK phosphorylates RLC in cortical actin bundles in fibroblasts (74). It is clear from these and other studies that localization of MLCK will play an important role in its biological functions.
The Ca2+ and calmodulin-dependent MLCK signaling pathway may represent one of several parallel pathways for regulation of myosin II activity in response to growth factors and adhesion proteins. Treatment of MCF-7 breast cancer cells with uPA, an activator of the MAPK pathway, stimulated cell migration, phosphorylation of MLCK, and myosin RLC, all of which were inhibited by a MEK inhibitor (75). These results are consistent with MAPK-mediated stimulation of MLCK activity by phosphorylation and resultant increases in cell migration (46). Interestingly, the ability of uPA to stimulate MCF-7 cell migration above basal values depended upon the engagement of specific integrins; a second class of integrins stimulated migration that was refractory to both uPA and MLCK inhibitors, indicating an alternate signaling pathway (75).
Growth factor signaling may lead to tyrosine phosphorylation of MLCK
(76). The N terminus of long MLCK contains an SH2-binding domain and a
consensus tyrosine phosphorylation site for Src. Treatment of
endothelial cells with diperoxovanadate decreased barrier function and
was associated with Src binding to cortactin and tyrosine
phosphorylation of MLCK (77, 78). Long MLCK containing phosphotyrosine
was also isolated from fibroblasts transfected by constitutively
activated epidermal growth factor receptor, v-Erb-B (79).
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Concluding Remarks |
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MLCK has served as a model for defining the enzyme activation
mechanism by the ubiquitous Ca2+ receptor, calmodulin, and
a wealth of biochemical, biophysical, and cellular information provides
insights into involved molecular processes. Recently identified
distinct isoforms of smooth muscle MLCK may regulate specific functions
of motility depending upon their respective intracellular locations and
Ca2+ sensitivities. The future holds exciting prospects for
identifying how networks of signaling pathways that regulate the actin
cytoskeleton control functionally important cellular properties of long
and short MLCKs.
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ACKNOWLEDGEMENTS |
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We gratefully acknowledge advice and help from Helen Yin, Anne Bresnick, Jill Trewhella, Joanna Krueger, and Sheng Ye in the preparation of this manuscript.
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Note Added in Proof |
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A recent report shows phosphorylation of specific tyrosine residues in the N-terminal extension of long MLCK by p60src increases kinase activity (81).
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FOOTNOTES |
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* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001. This is the fourth article of four in the "Ca2+-dependent Cell Signaling through Calmodulin-activated Protein Phosphatase and Protein Kinases Minireview Series." The work from the authors was funded by the National Institutes of Health.
To whom correspondence should be addressed. Tel.: 214-648-6849;
E-mail: James.Stull@UTSouthwestern.edu.
Published, JBC Papers in Press, November 28, 2000, DOI 10.1074/jbc.R000028200
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ABBREVIATIONS |
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The abbreviations used are:
[Ca2+]i, intracellular calcium concentration;
MLCK, myosin light chain kinase;
RLC, regulatory light chain of myosin
II;
Fn, fibronectin;
PEVK, repeat sequences rich in Phe, Glu,
Val, and Lys residues;
kb, kilobase(s);
KCaM, concentration of Ca2+/calmodulin required for half-maximal
activation;
CaMK II, Ca2+/calmodulin-dependent
protein kinase II;
PAK, p21-activated kinase;
MAPK, mitogen-activated
protein kinase;
GTPS, guanosine
5'-3-O-(thio)triphosphate;
MEK, MAPK/extracellular
signal-regulated kinase kinase;
uPA, urokinase-type plasminogen
activator.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1. | Kamm, K. E., and Stull, J. T. (1985) Annu. Rev. Pharmacol. Toxicol. 25, 593-620[CrossRef][Medline] [Order article via Infotrieve] |
2. | Hartshorne, D. J. (1987) in Physiology of the Gastrointestinal Tract (Johnson, L. R., ed) , pp. 423-482, Raven Press, New York |
3. | Stull, J. T., Lin, P. J., Krueger, J. K., Trewhella, J., and Zhi, G. (1998) Acta Physiol. Scand. 164, 471-482[Medline] [Order article via Infotrieve] |
4. | Schoenwaelder, S. M., and Burridge, K. (1999) Curr. Opin. Cell Biol. 11, 274-286[CrossRef][Medline] [Order article via Infotrieve] |
5. | Bresnick, A. R. (1999) Curr. Opin. Cell Biol. 11, 26-33[CrossRef][Medline] [Order article via Infotrieve] |
6. |
Szaszi, K.,
Kurashima, K.,
Kapus, A.,
Paulsen, A.,
Kaibuchi, K.,
Grinstein, S.,
and Orlowski, J.
(2000)
J. Biol. Chem.
275,
28599-28606 |
7. |
Aromolaran, A. S.,
Albert, A. P.,
and Large, W. A.
(2000)
J. Physiol. (Lond.)
524,
853-863 |
8. | Tran, Q.-K., Watanabe, H., Zhang, X.-X., Takahashi, T., and Ohno, R. (1999) Cardiovasc. Res. 44, 623-631[CrossRef][Medline] [Order article via Infotrieve] |
9. |
Sato, M.,
Tani, E.,
Fujikawa, H.,
and Kaibuchi, K.
(2000)
Circ. Res.
87,
195-200 |
10. |
van Nieuw Amerongen, G. P.,
van Delft, S.,
Vermeer, M. A.,
Collard, J. G.,
and van Hinsbergh, V. W. M.
(2000)
Circ. Res.
87,
335-340 |
11. |
Ammit, A. J.,
Armour, C. L.,
and Black, J. L.
(2000)
Am. J. Respir. Crit. Care Med.
161,
257-263 |
12. | Birukov, K. G., Schavocky, J. P., Shirinsky, V. P., Chibalina, M. V., Van Eldik, L. J., and Watterson, D. M. (1998) J. Cell. Biochem. 70, 402-413[CrossRef][Medline] [Order article via Infotrieve] |
13. | Watterson, D. M., Schavocky, J. P., Guo, L., Weiss, C., Chlenski, A., Shirinsky, V. P., Van Eldik, L. J., and Haiech, J. (1999) J. Cell. Biochem. 75, 481-491[CrossRef][Medline] [Order article via Infotrieve] |
14. |
Smith, A. F.,
Bigsby, R. M.,
Word, R. A.,
and Herring, N. T.
(1998)
Am. J. Physiol.
274,
C1188-C1195 |
15. | Champagne, M. B., Edwards, K. A., Erickson, H. P., and Kiehart, D. P. (2000) J. Mol. Biol. 300, 759-777[CrossRef][Medline] [Order article via Infotrieve] |
16. |
Lin, P.,
Luby-Phelps, K.,
and Stull, J. T.
(1999)
J. Biol. Chem.
274,
5987-5994 |
17. |
Ye, L. H.,
Hayakawa, K.,
Kishi, H.,
Imamura, M.,
Nakamura, A.,
Okagaki, T.,
Takagi, T.,
Iwata, A.,
Tanaka, T.,
and Kohama, K.
(1997)
J. Biol. Chem.
272,
32182-32189 |
18. |
Smith, L.,
Su, X.,
Lin, P.,
Zhi, G.,
and Stull, J. T.
(1999)
J. Biol. Chem.
274,
29433-29438 |
19. | Smith, L., and Stull, J. T. (2000) FEBS Lett. 480, 298-300[CrossRef][Medline] [Order article via Infotrieve] |
20. |
Herring, B. P.,
Dixon, S.,
and Gallagher, P. J.
(2000)
Am. J. Physiol.
279,
C1656-C1664 |
21. | Kudryashov, D. S., Chibalina, M. V., Birukov, K. G., Lukas, T. J., Sellers, J. R., Van Eldik, L. J., Watterson, D. M., and Shirinsky, V. P. (1999) FEBS Lett. 463, 67-71[CrossRef][Medline] [Order article via Infotrieve] |
22. | Fisher, S. A., and Ikebe, M. (1995) Biochem. Biophys. Res. Commun. 217, 696-703[CrossRef][Medline] [Order article via Infotrieve] |
23. |
Verin, A. D.,
Lazar, V.,
Torry, R. J.,
Labarrere, C. A.,
Patterson, C. E.,
and Garcia, J. G. N.
(1998)
Am. J. Respir. Cell Mol. Biol.
19,
758-766 |
24. |
Gallagher, P. J.,
Herring, B. P.,
Griffin, S. A.,
and Stull, J. T.
(1991)
J. Biol. Chem.
266,
23936-23944 |
25. |
Wu, X.,
Haystead, T. A.,
Nakamoto, R. K.,
Somlyo, A. V.,
and Somlyo, A. P.
(1998)
J. Biol. Chem.
273,
11362-11369 |
26. | Mayans, O., van der Ven, P. F., Wilm, M., Mues, A., Young, P., Furst, D. O., Wilmanns, M., and Gautel, M. (1998) Nature 395, 863-869[CrossRef][Medline] [Order article via Infotrieve] |
27. | Heierhorst, J., Kobe, B., Feil, S. C., Parker, M. W., Benian, G. M., Weiss, K. R., and Kemp, B. E. (1996) Nature 380, 636-639[CrossRef][Medline] [Order article via Infotrieve] |
28. | Smith, J. L., Silveira, L. A., and Spudich, J. A. (1996) EMBO J. 15, 6075-6083[Abstract] |
29. | Heidorn, D. B., Seeger, P. A., Rokop, S. E., Blumenthal, D. K., Means, A. R., Crespi, H., and Trewhella, J. (1989) Biochemistry 28, 6757-6764[Medline] [Order article via Infotrieve] |
30. | Ikura, M., Clore, G. M., Gronenborn, A. M., Zhu, G., Klee, C. B., and Bax, A. (1992) Science 256, 632-638[Medline] [Order article via Infotrieve] |
31. | Meador, W. E., Means, A. R., and Quiocho, F. A. (1992) Science 257, 1251-1255[Medline] [Order article via Infotrieve] |
32. | Gallagher, S. C., Wall, M. E., Krueger, J. K., Stull, J. T., and Trewhella, J. (2000) Biochemistry in press |
33. |
Persechini, A.,
Yano, K.,
and Stemmer, P. M.
(2000)
J. Biol. Chem.
275,
4199-4204 |
34. |
Bayley, P. M.,
Findlay, W. A.,
and Martin, S. R.
(1996)
Protein Sci.
5,
1215-1228 |
35. | Krueger, J. K., Zhi, G., Stull, J. T., and Trewhella, J. (1998) Biochemistry 37, 13997-14004[CrossRef][Medline] [Order article via Infotrieve] |
36. |
Padre, R. C.,
and Stull, J. T.
(2000)
J. Biol. Chem.
275,
26665-26673 |
37. | Padre, R. C., and Stull, J. T. (2000) FEBS Lett. 472, 148-152[CrossRef][Medline] [Order article via Infotrieve] |
38. | Tanaka, M., Ikebe, R., Matsuura, M., and Ikebe, M. (1995) EMBO J. 14, 2839-2846[Abstract] |
39. |
Zhi, G.,
Abdullah, S. M.,
and Stull, J. T.
(1998)
J. Biol. Chem.
273,
8951-8957 |
40. | Chin, D., Schreiber, J. L., and Means, A. R. (1999) Biochemistry 38, 15061-15069[CrossRef][Medline] [Order article via Infotrieve] |
41. | Chin, D., and Means, A. R. (2000) Trends Cell Biol. 10, 322-328[CrossRef][Medline] [Order article via Infotrieve] |
42. |
Conti, M. A.,
and Adelstein, R. S.
(1981)
J. Biol. Chem.
256,
3178-3181 |
43. |
Nishikawa, M.,
Shirakawa, S.,
and Adelstein, R. S.
(1985)
J. Biol. Chem.
260,
8978-8983 |
44. | Hashimoto, Y., and Soderling, T. R. (1990) Arch. Biochem. Biophys. 278, 41-45[Medline] [Order article via Infotrieve] |
45. |
Goeckeler, Z. M.,
Masaracchia, R. A.,
Zeng, Q.,
Chew, T. L.,
Gallagher, P.,
and Wysolmerski, R. B.
(2000)
J. Biol. Chem.
275,
18366-18374 |
46. |
Klemke, R. L.,
Cai, S.,
Giannini, A. L.,
Gallagher, P. J.,
de Lanerolle, P.,
and Cheresh, D. A.
(1997)
J. Cell Biol.
137,
481-492 |
47. | Morrison, D. L., Sanghera, J. S., Stewart, J., Sutherland, C., Walsh, M. P., and Pelech, S. L. (1996) Biochem. Cell Biol. 74, 549-557[Medline] [Order article via Infotrieve] |
48. | McDaniel, N. L., Rembold, C. M., and Murphy, R. A. (1994) Can. J. Physiol. Pharmacol. 72, 1380-1385[Medline] [Order article via Infotrieve] |
49. |
Tansey, M. G.,
Luby-Phelps, K.,
Kamm, K. E.,
and Stull, J. T.
(1994)
J. Biol. Chem.
269,
9912-9920 |
50. |
Somlyo, A. P.,
and Somlyo, A. V.
(2000)
J. Physiol. (Lond.)
522,
177-185 |
51. | Kimura, K., Ito, M., Amano, M., Chihara, K., Fukata, Y., Nakafuku, M., Yamamori, B., Feng, J., Nakano, T., Okawa, K., Iwamatsu, A., and Kaibuchi, K. (1996) Science 273, 245-248[Abstract] |
52. |
Ichikawa, K.,
Ito, M.,
and Hartshorne, D. J.
(1996)
J. Biol. Chem.
271,
4733-4740 |
53. | Eto, M., Ohmori, T., Suzuki, M., Furuya, K., and Morita, F. (1995) J. Biochem. (Tokyo) 118, 1104-1107[Abstract] |
54. | Kotlikoff, M. I., and Kamm, K. E. (1996) Annu. Rev. Physiol. 58, 115-141[CrossRef][Medline] [Order article via Infotrieve] |
55. |
Tang, D. C.,
Stull, J. T.,
Kubota, Y.,
and Kamm, K. E.
(1992)
J. Biol. Chem.
267,
11839-11845 |
56. |
Van Riper, D. A.,
Weaver, B. A.,
Stull, J. T.,
and Rembold, C. M.
(1995)
Am. J. Physiol.
268,
H2466-H2475 |
57. | Rokolya, A., and Singer, H. A. (2000) Am. J. Physiol. 278, C537-C545 |
58. |
Kim, I.,
Je, H. D.,
Gallant, C.,
Zhan, Q.,
Riper, D. V.,
Badwey, J. A.,
Singer, H. A.,
and Morgan, K. G.
(2000)
J. Physiol. (Lond.)
526,
367-374 |
59. | McCarron, J. G., McGeown, J. G., Reardon, S., Ikebe, M., Fay, F. S., and Walsh, J. V., Jr. (1992) Nature 357, 74-77[CrossRef][Medline] [Order article via Infotrieve] |
60. | Dzhura, I., Wu, Y., Colbran, R. J., Balser, J. R., and Anderson, M. E. (2000) Nat. Cell Biol. 2, 173-177[CrossRef][Medline] [Order article via Infotrieve] |
61. | Tang, D. C., Kubota, Y., Kamm, K. E., and Stull, J. T. (1993) FEBS Lett. 331, 272-275[CrossRef][Medline] [Order article via Infotrieve] |
62. |
Pettit, E. J.,
and Fay, F. S.
(1998)
Physiol. Rev.
78,
949-967 |
63. | Kaibuchi, K., Kuroda, S., and Amano, M. (1999) Annu. Rev. Biochem. 68, 459-486[CrossRef][Medline] [Order article via Infotrieve] |
64. | Aspenstrom, P. (1999) Curr. Opin. Cell Biol. 11, 95-102[CrossRef][Medline] [Order article via Infotrieve] |
65. |
Walker, J. W.,
Gilbert, S. H.,
Drummond, R. M.,
Yamada, M.,
Sreekumar, R.,
Carraway, R. E.,
Ikebe, M.,
and Fay, F. S.
(1998)
Proc. Natl. Acad. Sci. U. S. A.
95,
1568-1573 |
66. |
Kishi, H.,
Mikawa, T.,
Seto, M.,
Sasaki, Y.,
Kanayasu-Toyoda, T.,
Yamaguchi, T.,
Imamura, M.,
Ito, M.,
Karaki, H.,
Bao, J.,
Nakamura, A.,
Ishikawa, R.,
and Kohama, K.
(2000)
J. Biol. Chem.
275,
1414-1420 |
67. |
Poperechnaya, A.,
Varlamova, O.,
Lin, P.-J.,
Stull, J. T.,
and Bresnick, A. R.
(2000)
J. Cell Biol.
151,
697-709 |
68. | Lamb, N. J., Fernandez, A., Conti, M. A., Adelstein, R., Glass, D. B., Welch, W. J., and Feramisco, J. R. (1988) J. Cell Biol. 106, 1955-1971[Abstract] |
69. | Burridge, K., and Chrzanowska-Wodnicka, M. (1996) Annu. Rev. Cell Dev. Biol. 12, 463-518[CrossRef][Medline] [Order article via Infotrieve] |
70. |
Sanders, L. C.,
Matsumura, F.,
Bokoch, G. M.,
and de Lanerolle, P.
(1999)
Science
283,
2083-2085 |
71. |
Sells, M. A.,
Boyd, J. T.,
and Chernoff, J.
(1999)
J. Cell Biol.
145,
837-849 |
72. |
Kiosses, W. B.,
Daniels, R. H.,
Otey, C.,
Bokoch, G. M.,
and Schwartz, M. A.
(1999)
J. Cell Biol.
147,
831-844 |
73. | Chew, T. L., Masaracchia, R. A., Goeckeler, Z. M., and Wysolmerski, R. B. (1998) J. Muscle Res. Cell Motil. 19, 839-854[CrossRef][Medline] [Order article via Infotrieve] |
74. |
Totsukawa, G.,
Yamakita, Y.,
Yamashiro, S.,
Hartshorne, D. J.,
Sasaki, Y.,
and Matsumura, F.
(2000)
J. Cell Biol.
150,
797-806 |
75. |
Nguyen, D. H.,
Catling, A. D.,
Webb, D. J.,
Sankovic, M.,
Walker, L. A.,
Somlyo, A. V.,
Weber, M. J.,
and Gonias, S. L.
(1999)
J. Cell Biol.
146,
149-164 |
76. |
Cho, S. Y.,
and Klemke, R. L.
(2000)
J. Cell Biol.
149,
223-236 |
77. | Garcia, J. G., Verin, A. D., Schaphorst, K., Siddiqui, R., Patterson, C. E., Csortos, C., and Natarajan, V. (1999) Am. J. Physiol. 276, L989-L998[Medline] [Order article via Infotrieve] |
78. |
Shi, S.,
Garcia, J. G.,
Roy, S.,
Parinandi, N. L.,
and Natarajan, V.
(2000)
Am. J. Physiol.
279,
L441-L451 |
79. |
McManus, M. J.,
Boerner, J. L.,
Danielsen, A. J.,
Wang, Z.,
Matsumura, F.,
and Maihle, N. J.
(2000)
J. Biol. Chem.
275,
35328-32334 |
80. | Lazar, V., and Garcia, J. G. (1999) Genomics 57, 256-267[CrossRef][Medline] [Order article via Infotrieve] |
81. | Birukov, K. G., Csortos, C., Marzilli, L., Dudek, S., Ma, S-F., Bresnick, A. R., Verin, A. D., Cotter, R. J., and Garcia, J. G. N. (December 11, 2000) J. Biol. Chem. 10.1074/jbc.m005270200 |