γ-Secretase-dependent proteolysis of CD44 promotes neoplastic transformation of rat fibroblastic cells
γ-Secretase-dependent proteolysis of CD44 promotes neoplastic transformation of rat fibroblastic cells
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DOI：
10.1158/0008-5472.can-05-3870
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发表时间：
2006-04-01
期刊：
影响因子：
11.2
通讯作者：
Manié, SN
中科院分区：
文献类型：
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作者：
Pelletier, L;Guillaumot, P;Manié, SN
粘附分子CD 44的金属蛋白酶依赖性胞外域切割在人类肿瘤中经常观察到，并被认为促进转移。这种切割之后是CD 44胞内结构域（CD 44-ICD）的γ-分泌酶依赖性释放，其表现出核信号传导活性。使用可逆的Ret-dependent致癌转换模型，它限制了蛋白质的方法，我们确定了大鼠-1细胞的肿瘤转化和标准CD 44的表达之间的正相关性。在这些转化细胞中，发现CD 44经历连续的金属蛋白酶和γ-分泌酶切割，导致CD 44-ICD表达增加。我们发现这个蛋白水解片段具有转化活性。为了支持这一作用，它意义重大。在药物介导的γ-分泌酶抑制后，观察到Rat-1细胞的RET诱导转化的特异性减少。综上所述，这些发现表明，CD 44的脱落不仅可以调节转移，而且还通过释放CD 44-ICD影响肿瘤发生的早期事件。
The metalloprotease-dependent extracellular domain cleavage of the adhesion molecule CD44 is frequently observed in human tumors and is thought to promote metastasis. This cleavage is followed by gamma-secretase-dependent release of CD44 intracellular domain (CD44-ICD), which exhibits nuclear signaling activity. Using a reversible Ret-dependent oncogenic conversion model and it restricted protemnic approach, we identified a positive correlation between the neoplastic transformation of Rat-1 cells and the expression of standard CD44. In these transformed cells, CD44 was found to undergo a sequential metalloprotease and gamma-secretase cleavage, resulting in an increase in expression of CD44-ICD. We showed that this proteolytic fragment possesses at transforming activity. In support of this role, it significant. and specific reduction in Ret-induced transformation of Rat-1 cells was observed following drug-mediated inhibition of gamma-secretase. Taken together, these findings suggest that the shedding of CD44 may not only modulate metastasis but also affects earlier events in tumorigenesis through the release of CD44-ICD.