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Ca 2+ ‐independent phospholipase A2‐dependent sustained Rho‐kinase activation exhibits all‐or‐none response
Author(s) -
Maeda Akio,
Ozaki Yuichi,
Sivakumaran Sudhir,
Akiyama Tetsuro,
Urakubo Hidetoshi,
Usami Ayako,
Sato Miharu,
Kaibuchi Kozo,
Kuroda Shinya
Publication year - 2006
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2006.01001.x
Subject(s) - rho associated protein kinase , phosphorylation , microbiology and biotechnology , biology , myosin light chain phosphatase , myosin light chain kinase , kinase , phospholipase a2 , in vivo , protein kinase a , myosin , in silico , phospholipase , biochemistry , enzyme , gene
Sustained contraction of cells depends on sustained Rho‐associated kinase (Rho‐kinase) activation. We developed a computational model of the Rho‐kinase pathway to understand the systems characteristics. Thrombin‐dependent in vivo transient responses of Rho activation and Ca 2+ increase could be reproduced in silico . Low and high thrombin stimulation induced transient and sustained phosphorylation, respectively, of myosin light chain (MLC) and myosin phosphatase targeting subunit 1 (MYPT1) in vivo . The transient phosphorylation of MLC and MYPT1 could be reproduced in silico , but their sustained phosphorylation could not. This discrepancy between in vivo and in silico in the sustained responses downstream of Rho‐kinase indicates that a missing pathway(s) may be responsible for the sustained Rho‐kinase activation. We found, experimentally, that the sustained phosphorylation of MLC and MYPT1 exhibit all‐or‐none responses. Bromoenol lactone, a specific inhibitor of Ca 2+ ‐independent phospholipase A2 (iPLA2), inhibited sustained phosphorylation of MLC and MYPT1, which indicates that sustained Rho‐kinase activation requires iPLA2 activity. Thus, the systems analysis of the Rho‐kinase pathway identified a novel iPLA2‐dependent mechanism of the sustained Rho‐kinase activation, which exhibits an all‐or‐none response.