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Blood, Vol. 95 No. 7 (April 1), 2000:
pp. 2407-2412
Regulation of polymorphonuclear leukocyte phagocytosis by myosin
light chain kinase after activation of mitogen-activated protein kinase
Pamela J. Mansfield,
James A. Shayman, and
Laurence A. Boxer
From the Departments of Pediatrics and Internal Medicine, University
of Michigan, Ann Arbor, MI.
Polymorphonuclear leukocyte (PMNL) phagocytosis
mediated by Fc RII proceeds in concert with activation of the
mitogen-activated protein (MAP) kinase, extracellular signal-regulated
kinase ERK2. We hypothesized that myosin light chain kinase (MLCK)
could be phosphorylated and activated by ERK, thereby
linking the MAP kinase pathway to the activation of cytoskeletal
components required for pseudopod formation. To explore this
potential linkage, PMNLs were challenged with
antibody-coated erythrocytes (EIgG). Peak MLCK activity, 3-fold
increased over controls, occurred at 4 to 6 minutes,
corresponding with the peak rate of target ingestion and ERK2
activity. The MLCK inhibitor ML-7 (10 µmol/L) inhibited both phagocytosis and MLCK activity to basal values, thereby providing further support for the linkage between the functional response and the
requirement for MLCK activation. The MAPK kinase (MEK) inhibitor
PD098059 inhibited phagocytosis, MLCK activity, and ERK2 activity
by 80% to 90%. To directly link ERK activation to MLCK activation,
ERK2 was immunoprecipitated from PMNLs after EIgG ingestion. The
isolated ERK2 was incubated with PMNL cytosol as a source of
unactivated MLCK and with MLCK substrate; under these conditions ERK2
activated MLCK, resulting in phosphorylation of the MLCK substrate or
of the myosin light chain itself. Because MLCK activates myosin,
we evaluated the effect of directly inhibiting myosin
adenosine triphosphatase using 2,3-butanedione monoxime (BDM) and
found that phagocytosis was inhibited by more than 90% but MLCK
activity remained unaffected. These results are consistent with the
interpretation that MEK activates ERK, ERK2 then activates MLCK, and
MLCK activates myosin. MLCK activation is a critical step in the
cytoskeletal changes resulting in pseudopod formation.
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