alexa Arrest defective-1 controls tumor cell behavior by acetylating myosin light chain kinase.
Reproductive Medicine

Reproductive Medicine

Reproductive System & Sexual Disorders: Current Research

Author(s): Shin DH, Chun YS, Lee KH, Shin HW, Park JW

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Abstract BACKGROUND: The enhancement of cell motility is a critical event during tumor cell spreading. Since myosin light chain kinase (MLCK) regulates cell behavior, it is regarded as a promising target in terms of preventing tumor invasion and metastasis. Since MLCK was identified to be associated with human arrest defective-1 (hARD1) through yeast two-hybrid screening, we here tested the possibility that hARD1 acts as a regulator of MLCK and by so doing controls tumor cell motility. METHODOLOGY/PRINCIPAL FINDINGS: The physical interaction between MLCK and hARD1 was confirmed both in vivo and in vitro by immunoprecipitation assay and affinity chromatography. hARD1, which is known to have the activity of protein lysine epsilon-acetylation, bound to and acetylated MLCK activated by Ca(2+) signaling, and by so doing deactivated MLCK, which led to a reduction in the phosphorylation of MLC. Furthermore, hARD1 inhibited tumor cell migration and invasion MLCK-dependently. Our mutation study revealed that hARD1 associated with an IgG motif of MLCK and acetylated the Lys608 residue in this motif. The K608A-mutated MLCK was neither acetylated nor inactivated by hARD1, and its stimulatory effect on cell motility was not inhibited by hARD1. CONCLUSION/SIGNIFICANCE: These results indicate that hARD1 is a bona fide regulator of MLCK, and that hARD1 plays a crucial role in the balance between tumor cell migration and stasis. Thus, hARD1 could be a therapeutic target in the context of preventing tumor invasion and metastasis.
This article was published in PLoS One and referenced in Reproductive System & Sexual Disorders: Current Research

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