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A reassessment of the inhibitory capacity of human FKBP38 on calcineurin
Author(s) -
Weiwad Matthias,
Edlich Frank,
Erdmann Frank,
Jarczowski Franziska,
Kilka Susann,
Dorn Madlen,
Pechstein Arndt,
Fischer Gunter
Publication year - 2005
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/j.febslet.2004.12.098
Subject(s) - calcineurin , phosphatase , fkbp , microbiology and biotechnology , biochemistry , signal transduction , immunoprecipitation , biology , chemistry , phosphorylation , transplantation , gene , medicine , surgery
The microbial peptidomacrolide FK506 affects many eukaryotic developmental and cell signaling programs via calcineurin inhibition. Prior formation of a complex between FK506 and intracellular FK506‐binding proteins (FKBPs) is the precondition for the interaction with calcineurin. A puzzling difference has emerged between the mammalian multidomain protein h FKBP38 and other FKBPs. It was shown that h FKBP38 not only binds to calcineurin but also inhibits the protein phosphatase activity of calcineurin on its own [Shirane, M. and Nakayama, K.I. (2003) Nature Cell Biol. 5, 28–37]. Inherent calcineurin inhibition by h FKBP38 would completely eliminate the need for FK506 in controlling many signal transduction pathways. To address this issue, we have characterized the functional and physical interactions between calcineurin and h FKBP38. A recombinant h FKBP38 variant and endogenous h FKBP38 were tested both in vitro and in vivo. The proteins neither directly inhibited calcineurin activity nor affected NFAT reporter gene activity in SH‐SY5Y and Jurkat cells. In addition, a direct physical interaction between calcineurin and h FKBP38 was not detected in co‐immunoprecipitation experiments. However, h FKBP38 indirectly affected the subcellular distribution of calcineurin by interaction with typical calcineurin ligands, as exemplified by the anti‐apoptotic protein Bcl‐2. Our data suggest that h FKBP38 cannot substitute for the FKBP/FK506 complex in signaling pathways controlled by the protein phosphatase activity of calcineurin.