Phosphorylated hamartin-Hsp70 complex regulates apoptosis via mitochondrial localization

被引：6

作者：

Inoue, Hirofumi ^{[1
]}

Uyama, Takumi ^{[1
]}

Suzuki, Tsukasa ^{[1
]}

Kazami, Machiko ^{[1
]}

Hino, Okio ^{[2
]}

Kobayashi, Toshiyuki ^{[2
]}

Kobayashi, Ken-Ichi ^{[1
]}

Tadokoro, Tadahiro ^{[1
]}

Yamamoto, Yuji ^{[1
]}

机构：

[1] Tokyo Univ Agr, Dept Appl Biol & Chem, Setagaya Ku, Tokyo 1568502, Japan

[2] Juntendo Univ, Dept Pathol & Oncol, Sch Med, Bunkyo Ku, Tokyo 1138421, Japan

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2010年 / 391卷 / 01期

关键词：

Hamartin; Phosphorylation; Hsp70; Mitochondria; Apoptosis; GENE-PRODUCT; TUBERIN PHOSPHORYLATION; TSC2; PROTEIN; IDENTIFICATION; EXPRESSION; INHIBITOR; MUTATION; GRIM-19; GTPASE;

D O I：

10.1016/j.bbrc.2009.12.054

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The products of the tuberous sclerosis complex (TSC) genes, hamartin and tuberin, form a heterodimer. Recently we reported that hamartin directly interacted with Hsp70. However, the physiological implications of this interaction have not yet been clearly defined. Here we show that hamartin localized to the outer membrane of the mitochondria in an Hsp70-dependent manner. Moreover, phosphorylation of the T417 residue of hamartin was required for its localization to the mitochondria as well as its interaction with Hsp70. A non-phosphorylatable hamartin mutant at residue T417 was unable to localize to the mitochondria and suppress apoptosis, whereas non-phosphorylatable hamartin mutants T357A and T390A localized to the mitochondria and suppressed apoptosis. Importantly, non-phosphorylatable mutants (T357A, T390A and T417A) promoted apoptosis after treatment with Hsp 70-inhibitor KNK437. We conclude that hamartin inhibited apoptosis by localizing to the mitochondria and that its phosphorylation and binding to Hsp70 was required for facilitation of this process. (C) 2009 Elsevier Inc. All rights reserved.

引用

页码：1148 / 1153

页数：6

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