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Role of tyrosine phosphorylation of phospholipase C γ1 in the signaling pathway of HMG‐CoA reductase inhibitor‐induced cell death of L6 myoblasts
Author(s) -
Mutoh Tatsuro,
Kumano Takanori,
Nakagawa Hiroto,
Kuriyama Masaru
Publication year - 1999
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(99)00188-x
Subject(s) - tyrosine phosphorylation , simvastatin , phosphorylation , phospholipase c , tyrosine , microbiology and biotechnology , protein tyrosine phosphatase , tyrosine kinase , biology , tyrosine kinase inhibitor , phospholipase , signal transduction , chemistry , biochemistry , endocrinology , enzyme , genetics , cancer
Our previous studies have shown that the HMG‐CoA reductase (HCR) inhibitor (HCRI), simvastatin, kills L6 myoblasts by involving Ca 2+ mobilization from the Ca 2+ pool in the cells but not by influx from extracellular space. More recently, we found that HCRI induced tyrosine phosphorylation of several cellular proteins, followed by apoptotic cell death of L6 myoblasts. The present study was aimed to elucidate the molecular target(s) of these tyrosine phosphorylations induced by HCRI and demonstrated that simvastatin induces tyrosine phosphorylation of phospholipase C (PLC) γ1. This tyrosine phosphorylation of PLC‐γ1 caused the increment of the intracellular inositol triphosphate (IP3) levels in L6 myoblasts. Pretreatment of the cells with herbimycin A, a specific inhibitor of protein tyrosine kinase, inhibited a simvastatin‐induced increase in IP3 level in the cells as well as tyrosine phosphorylation of PLC‐γ1. Interestingly, pretreatment of the cells with U‐73122, a specific inhibitor of PLC, prevented simvastatin‐induced cell death. Thus, these results strongly suggest that simvastatin‐induced tyrosine phosphorylation of PLC‐γ1 plays, at least in part, an important role for the development of simvastatin‐induced cell death.