TSC1 controls distribution of actin fibers through its effect on function of Rho family of small GTPases and regulates cell migration and polarity.
TSC1 controls distribution of actin fibers through its effect on function of Rho family of small GTPases and regulates cell migration and polarity.
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DOI：
10.1371/journal.pone.0054503
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hino O
中科院分区：
文献类型：
--
作者：
Ohsawa M;Kobayashi T;Okura H;Igarashi T;Mizuguchi M;Hino O
肿瘤抑制基因TSC1和TSC2在结节性硬化症（常染色体显性多系统疾病）中发生突变。TSC1和TSC2的基因产物形成一种蛋白复合物，抑制哺乳动物雷帕霉素靶蛋白复合物1 （mTORC1）通路的信号传导。mTORC1是调控细胞生长、增殖和存活的关键分子。当TSC1/TSC2复合物不起作用时，不受控制的mTORC1活性会加速细胞周期并触发肿瘤发生。最近的研究表明，TSC1和TSC2还能调节小gtpase Rho家族成员Rac1和Rho的活性，从而影响局灶黏附时的肌动蛋白细胞骨架组织。然而，TSC1如何促进细胞极性的建立尚不清楚。本研究在稳定表达TSC1的细胞系中分析了TSC1与肌动蛋白细胞骨架形成之间的关系，这些细胞系最初是由TSC1缺陷小鼠肾肿瘤细胞系建立的。我们的分析表明，当TSC1表达时，细胞增殖和迁移受到抑制。这些细胞中的Rac1活性也随着板足和丝足的形成而降低。基底肌动蛋白应力纤维数量减少；相反，在表达tsc1的细胞中，起源于紧密连接水平的顶端肌动蛋白纤维形成了一个网络。rho激酶（ROCK）抑制剂减少了顶端肌动蛋白纤维的数量，但雷帕霉素没有影响。因此，肌动蛋白纤维是由Rho-ROCK通路独立于mTOR调控的。此外，抑制Rac1活性后，tsc1缺陷细胞中出现了顶端肌动蛋白纤维。这些结果表明，TSC1通过Rho家族的小gtpase的空间调控来调节细胞极性相关的肌动蛋白纤维的形成。
The tumor-suppressor genes TSC1 and TSC2 are mutated in tuberous sclerosis, an autosomal dominant multisystem disorder. The gene products of TSC1 and TSC2 form a protein complex that inhibits the signaling of the mammalian target of rapamycin complex1 (mTORC1) pathway. mTORC1 is a crucial molecule in the regulation of cell growth, proliferation and survival. When the TSC1/TSC2 complex is not functional, uncontrolled mTORC1 activity accelerates the cell cycle and triggers tumorigenesis. Recent studies have suggested that TSC1 and TSC2 also regulate the activities of Rac1 and Rho, members of the Rho family of small GTPases, and thereby influence the ensuing actin cytoskeletal organization at focal adhesions. However, how TSC1 contributes to the establishment of cell polarity is not well understood. Here, the relationship between TSC1 and the formation of the actin cytoskeleton was analyzed in stable TSC1-expressing cell lines originally established from a Tsc1-deficient mouse renal tumor cell line. Our analyses showed that cell proliferation and migration were suppressed when TSC1 was expressed. Rac1 activity in these cells was also decreased as was formation of lamellipodia and filopodia. Furthermore, the number of basal actin stress fibers was reduced; by contrast, apical actin fibers, originating at the level of the tight junction formed a network in TSC1-expressing cells. Treatment with Rho-kinase (ROCK) inhibitor diminished the number of apical actin fibers, but rapamycin had no effect. Thus, the actin fibers were regulated by the Rho-ROCK pathway independently of mTOR. In addition, apical actin fibers appeared in TSC1-deficient cells after inhibition of Rac1 activity. These results suggest that TSC1 regulates cell polarity-associated formation of actin fibers through the spatial regulation of Rho family of small GTPases.
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DOI：
10.1083/jcb.200403069
发表时间：
2004-07-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harrington LS;Findlay GM;Gray A;Tolkacheva T;Wigfield S;Rebholz H;Barnett J;Leslie NR;Cheng S;Shepherd PR;Gout I;Downes CP;Lamb RF
通讯作者：
Lamb RF
影响因子：
4.8
作者：
Larson, Yan;Liu, Jianyu;Gao, Tianyan
通讯作者：
Gao, Tianyan
影响因子：
4
作者：
Hildebrand, JD
通讯作者：
Hildebrand, JD
DOI：
10.1073/pnas.151033798
发表时间：
2001-07-17
影响因子：
11.1
作者：
Kobayashi, T;Minowa, O;Hino, O
通讯作者：
Hino, O
影响因子：
4
作者：
Deakin NO;Turner CE
通讯作者：
Turner CE