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Pleckstrin homology domain of p210 BCR ‐ ABL interacts with cardiolipin to regulate its mitochondrial translocation and subsequent mitophagy
Author(s) -
Shimasaki Kentaro,
WatanabeTakahashi Miho,
Umeda Masato,
Funamoto Satoru,
Saito Yoshiro,
Noguchi Noriko,
Kumagai Keigo,
Hanada Kentaro,
Tsukahara Fujiko,
Maru Yoshiro,
Shibata Norihito,
Naito Mikihiko,
Nishikawa Kiyotaka
Publication year - 2018
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/gtc.12544
Subject(s) - pleckstrin homology domain , biology , cardiolipin , mitophagy , microbiology and biotechnology , mitochondrion , biochemistry , signal transduction , autophagy , apoptosis , phospholipid , membrane
Chronic myeloid leukemia ( CML ) is caused by the chimeric protein p210 BCR ‐ ABL encoded by a gene on the Philadelphia chromosome. Although the kinase domain of p210 BCR ‐ ABL is an active driver of CML , the pathological role of its pleckstrin homology ( PH ) domain remains unclear. Here, we carried out phospholipid vesicle‐binding assays to show that cardiolipin ( CL ), a characteristic mitochondrial phospholipid, is a unique ligand of the PH domain. Arg726, a basic amino acid in the ligand‐binding region, was crucial for ligand recognition. A subset of wild‐type p210 BCR ‐ ABL that was transiently expressed in HEK 293 cells was dramatically translocated from the cytosol to mitochondria in response to carbonyl cyanide m ‐chlorophenylhydrazone ( CCCP ) treatment, which induces mitochondrial depolarization and subsequent externalization of CL to the organelle's outer membrane, whereas an R726A mutant of the protein was not translocated. Furthermore, only wild‐type p210 BCR ‐ ABL , but not the R726A mutant, suppressed CCCP ‐induced mitophagy and subsequently enhanced reactive oxygen species production. Thus, p210 BCR ‐ ABL can change its intracellular localization via interactions between the PH domain and CL to cope with mitochondrial damage. This suggests that p210 BCR ‐ ABL could have beneficial effects for cancer proliferation, providing new insight into the PH domain's contribution to CML pathogenesis.

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