Overexpression of caveolin-1 is sufficient to phenocopy the behavior of a disease-associated mutant.
Overexpression of caveolin-1 is sufficient to phenocopy the behavior of a disease-associated mutant.
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DOI：
10.1111/tra.12066
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发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
Kenworthy AK
中科院分区：
文献类型：
--
作者：
Hanson CA;Drake KR;Baird MA;Han B;Kraft LJ;Davidson MW;Kenworthy AK
小窝蛋白-1表达水平的突变和改变与许多人类疾病有关。小窝蛋白-1的失调如何导致疾病尚不完全清楚，但已提出涉及蛋白质突变形式的细胞内积累。为了更好地理解细胞内捕获小窝蛋白-1的运输缺陷的分子基础，我们比较了GFP标记的小窝蛋白-1 P132 L的性质，这是一种先前与乳腺癌相关的小窝蛋白-1突变形式，与野生型小窝蛋白-1。出乎意料的是，野生型小窝蛋白-1-GFP也积累在细胞内，使我们更详细地研究野生型和突变蛋白异常定位的机制。我们表明，标签和细胞环境的性质影响小窝蛋白-1的亚细胞分布，证明即使是野生型形式的小窝蛋白-1在某些条件下可以作为一个显性负功能，并确定特定的构象变化与不正确的目标形式的蛋白质。此外，我们发现细胞内小窝蛋白-1的Tyr 14磷酸化，但磷酸化不是蛋白质的误激活所必需的。这些发现确定了caveolin-1错误形式的新特性，并提出了与caveolin-1过度表达和突变相关的疾病的常见运输缺陷的可能性。
Mutations and alterations in caveolin-1 expression levels have been linked to a number of human diseases. How misregulation of caveolin-1 contributes to disease is not fully understood, but has been proposed to involve the intracellular accumulation of mutant forms of the protein. To better understand the molecular basis for trafficking defects that trap caveolin-1 intracellularly, we compared the properties of a GFP-tagged version of caveolin-1 P132L, a mutant form of caveolin-1 previously linked to breast cancer, with wild type caveolin-1. Unexpectedly, wild type caveolin-1-GFP also accumulated intracellularly, leading us to examine the mechanisms underlying the abnormal localization of the wild type and mutant protein in more detail. We show that both the nature of the tag and cellular context impact the subcellular distribution of caveolin-1, demonstrate that even the wild type form of caveolin-1 can function as a dominant negative under some conditions, and identify specific conformation changes associated with incorrectly targeted forms of the protein. In addition, we find intracellular caveolin-1 is phosphorylated on Tyr14, but phosphorylation is not required for mistrafficking of the protein. These findings identify novel properties of mistargeted forms of caveolin-1 and raise the possibility that common trafficking defects underlie diseases associated with overexpression and mutations in caveolin-1.
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影响因子：
56.9
作者：
Cole, NB;Smith, CL;LippincottSchwartz, J
通讯作者：
LippincottSchwartz, J
DOI：
10.1083/jcb.201003086
发表时间：
2010-11-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hayer A;Stoeber M;Ritz D;Engel S;Meyer HH;Helenius A
通讯作者：
Helenius A
DOI：
10.1073/pnas.92.19.8655
发表时间：
1995-09-12
影响因子：
11.1
作者：
FRA, AM;WILLIAMSON, E;PARTON, RG
通讯作者：
PARTON, RG
影响因子：
4.5
作者：
Hill, Michelle M.;Scherbakov, Nadja;Parat, Marie-Odile
通讯作者：
Parat, Marie-Odile
影响因子：
9.8
作者：
Boettcher, Jan Peter;Kirchner, Marieluise;Meyer, Thomas F.
通讯作者：
Meyer, Thomas F.