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J. Biol. Chem., Vol. 278, Issue 15, 13016-13025, April 11, 2003
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From the Department of Immunology, The Scripps Research Institute,
La Jolla, California 92037
Nonmotile cells extend and retract
pseudopodia-like structures in a random manner, whereas motile cells
establish a single dominant pseudopodium in the direction of movement.
This is a critical step necessary for cell migration and occurs prior
to cell body translocation, yet little is known about how this process is regulated. Here we show that myosin II light chain (MLC)
phosphorylation at its regulatory serine 19 is elevated in growing and
retracting pseudopodia. MLC phosphorylation in the extending
pseudopodium was associated with strong and persistent amplification of
extracellular-regulated signal kinase (ERK) and MLC kinase activity,
which specifically localized to the leading pseudopodium.
Interestingly, inhibition of ERK or MLC kinase activity prevented MLC
phosphorylation and pseudopodia extension but not
retraction. In contrast, inhibition of RhoA activity specifically
decreased pseudopodia retraction but not extension. Importantly,
inhibition of RhoA activity specifically blocked MLC phosphorylation
associated with retracting pseudopodia. Inhibition of either ERK or
RhoA signals prevents chemotaxis, indicating that both pathways
contribute to the establishment of cell polarity and migration.
Together, these findings demonstrate that ERK and RhoA are distinct
pathways that control pseudopodia extension and retraction,
respectively, through differential modulation of MLC phosphorylation
and contractile processes.
ERK and RhoA Differentially Regulate Pseudopodia Growth and
Retraction during Chemotaxis*
*
This work was supported by Breast Cancer Research Program
Grant 6KB-0046, American Cancer Society/Research Project Grant
99-180-01, and National Institutes of Health Grant 5 R29 CA78493 (to
R. L. K.) as well as National Institutes of Health Grant 5 T32
CA75924 (to A. A. B.). This is paper 14987-IMM from The
Scripps Research Institute.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Immunology,
SP-231, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La
Jolla, CA 92037. Tel.: 858-784-7750; Fax: 858-784-7785; E-mail:
klemke@scripps.edu.
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