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Tyrosine phosphorylation is crucial for growth signaling by tissue inhibitors of metalloproteinases (TIMP‐1 and TIMP‐2)
Author(s) -
Yamashita Kyoko,
Suzuki Mitsunori,
Iwata Hiroyuki,
Koike Teruhiko,
Hamaguchi Michinari,
Shinagawa Akira,
Noguchi Toshihide,
Hayakawa Taro
Publication year - 1996
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 - 10.1016/0014-5793(96)01066-6
Subject(s) - matrix metalloproteinase , phosphorylation , tyrosine phosphorylation , cancer research , tyrosine , microbiology and biotechnology , protein tyrosine phosphatase , signal transduction , chemistry , biology , biochemistry
[ 3 H]Thymidine (TdR) incorporation by human osteosarcoma cell line MG‐63 was significantly stimulated at as early as 3 h after the addition of either TIMP‐1 or TIMP‐2 alone. Maximum stimulation was attained at a concentration of either 20 ng/ml (0.71 nM) TIMP‐1 or 1.0 ng/ml (46 pM) TIMP‐2. Tyrosine kinase inhibitors such as genistein, erbstatin, and herbimycin A almost completely inhibited the [ 3 H]TdR incorporation stimulated by either of the TIMPs. However, essentially no effect was observed with H‐89, H‐7, bisindolylmaleimide and K‐252a. These inhibition studies suggest a crucial role for tyrosine kinase in the signal transduction of TIMPs. Phosphotyrosine‐containing proteins were significantly elevated by the treatment with both TIMPs. We also found that either TIMP stimulated an increase in mitogen‐activated protein (MAP) kinase activity, suggesting that MAP kinase plays a role in TIMP‐dependent growth signaling.