Regulated proteolysis of Trop2 drives epithelial hyperplasia and stem cell self-renewal via β-catenin signaling
Regulated proteolysis of Trop2 drives epithelial hyperplasia and stem cell self-renewal via β-catenin signaling
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DOI：
10.1101/gad.196451.112
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发表时间：
2012-10-15
影响因子：
10.5
通讯作者：
Witte, Owen N.
中科院分区：
文献类型：
--
作者：
Stoyanova, Tanya;Goldstein, Andrew S.;Witte, Owen N.
细胞表面蛋白Trop2在未成熟的干细胞/祖细胞样细胞上表达，并在许多上皮癌中过表达。然而，Trop2在组织维持和肿瘤发生中的生物学功能尚不清楚。在这项研究中，我们证明了Trop2是自我更新、增殖和转化的调节因子。Trop2通过调节的膜内蛋白水解机制控制这些过程，导致Trop2的裂解，产生两个产物：细胞外结构域和细胞内结构域。Trop2的胞内结构域从细胞膜中释放出来并在细胞核中积累。Trop2细胞内结构域的高表达通过β -连环蛋白的信号传导促进了干细胞/祖细胞的自我更新，并足以在体内启动前列腺癌的前体病变。重要的是，我们证明了b-连环蛋白或Trop2功能缺失切割突变体的缺失会消除前列腺中Trop2驱动的自我更新和增生。这些发现表明，在上皮癌中，Trop2的高表达被选择来增强自我更新和增殖的茎样特性。明确Trop2在自我更新和转化中的功能机制对于确定阻断Trop2在癌症中的激活的新治疗策略至关重要。
The cell surface protein Trop2 is expressed on immature stem/progenitor-like cells and is overexpressed in many epithelial cancers. However the biological function of Trop2 in tissue maintenance and tumorigenesis remains unclear. In this study, we demonstrate that Trop2 is a regulator of self-renewal, proliferation, and transformation. Trop2 controls these processes through a mechanism of regulated intramembrane proteolysis that leads to cleavage of Trop2, creating two products: the extracellular domain and the intracellular domain. The intracellular domain of Trop2 is released from the membrane and accumulates in the nucleus. Heightened expression of the Trop2 intracellular domain promotes stem/progenitor self-renewal through signaling via beta-catenin and is sufficient to initiate precursor lesions to prostate cancer in vivo. Importantly, we demonstrate that loss of b-catenin or Trop2 loss-of-function cleavage mutants abrogates Trop2-driven self-renewal and hyperplasia in the prostate. These findings suggest that heightened expression of Trop2 is selected for in epithelial cancers to enhance the stem-like properties of self-renewal and proliferation. Defining the mechanism of Trop2 function in self-renewal and transformation is essential to identify new therapeutic strategies to block Trop2 activation in cancer.