Nuclear and cytoplasmic c-Ski differently modulate cellular functions
Nuclear and cytoplasmic c-Ski differently modulate cellular functions
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DOI：
10.1111/j.1365-2443.2006.01018.x
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发表时间：
2006-11-01
期刊：
影响因子：
2.1
通讯作者：
Miyazono, Kohei
中科院分区：
文献类型：
--
作者：
Nagata, Motoko;Goto, Kouichiro;Miyazono, Kohei
c-Ski是一种原癌基因产物，当其在间充质细胞中过度表达时，可诱导形态转化、锚定独立性和肌源性分化。c-Ski还通过与Smad蛋白的相互作用抑制转化生长因子- β (tgf - β)超家族成员的信号传导。虽然c-Ski主要定位于细胞核，但在一些肿瘤组织和细胞系中也报道了其异常的细胞质定位。在本研究中，我们鉴定了c-Ski的核定位信号（NLS）。通过引入一个突变来消除NLS活性，我们研究了细胞质c-Ski的功能。尽管细胞质c-Ski通过将活化的Smad复合物分离到细胞质上，抑制了tgf - β超家族诱导的Smad信号传导，但它未能表现出一些需要c-Ski核定位的活性，包括抑制Smad7基因的基础转录。这些发现表明c-Ski的亚细胞定位影响其生物活性。我们还发现，当蛋白酶体活性被抑制时，c-Ski在细胞质中积累。蛋白酶体抑制剂在细胞质积累所需区域的定位表明，c-Ski的亚细胞定位可能受到蛋白酶体敏感过程通过氨基酸残基94-210和491-548的调节。
c-Ski is a proto-oncogene product that induces morphologic transformation, anchorage independence, and myogenic differentiation when it is over-expressed in mesenchymal cells. c-Ski also inhibits signaling of transforming growth factor-beta (TGF-beta) superfamily members through interaction with Smad proteins. Although c-Ski is predominantly localized in the nucleus, aberrant cytoplasmic localization of it has also been reported in some tumor tissues and cell lines. In the present study, we identified the nuclear localization signal (NLS) in c-Ski. By introducing a mutation to abolish NLS activity, we examined the function of cytoplasmic c-Ski. Although cytoplasmic c-Ski suppressed TGF-beta superfamily-induced Smad signaling through sequestration of activated Smad complex to the cytoplasm, it failed to exhibit some of the activities that require nuclear localization of c-Ski, including suppression of basal transcription of the Smad7 gene. These findings indicate that subcellular localization of c-Ski affects its biologic activities. We also found that c-Ski accumulated in the cytoplasm when proteasome activity was inhibited. Mapping of the regions required for cytoplasmic accumulation by proteasome inhibitors suggests that subcellular localization of c-Ski may be regulated by proteasome-sensitive processes through amino acid residues 94-210 and 491-548.