Vestigial-like family member 3 (VGLL3), a cofactor for TEAD transcription factors, promotes cancer cell proliferation by activating the Hippo pathway
Vestigial-like family member 3 (VGLL3), a cofactor for TEAD transcription factors, promotes cancer cell proliferation by activating the Hippo pathway
复制标题
DOI：
10.1074/jbc.ra120.012781
复制
发表时间：
2020-06-26
影响因子：
4.8
通讯作者：
Yamaguchi, Noritaka
中科院分区：
文献类型：
--
作者：
Hori, Naoto;Okada, Kazuyuki;Yamaguchi, Noritaka
残留样蛋白3(VGLL3)是VGLL家族中的一员，其成员是含有茶叶结构域的转录因子(Teads)的辅助因子。TEAD与辅因子是相关蛋白(YAP)和带有PDZ结合基序的转录共激活因子(TAZ)一起促进组织和肿瘤的发展。虽然VGLL3参与了肿瘤细胞的增殖，但它与Teads和YAP/TAZ的关系仍不清楚。为了缩小这一研究差距，我们在这里建立了稳定表达VGLL3的肿瘤细胞，并发现它们表现出增强的增殖。值得注意的是，在表达VGLL3的细胞中，YAP和TAZ被灭活，这与抑制YAP/TAZ活性的Hippo途径的激活相一致。VGLL3联合Teads可促进河马通路成分大肿瘤抑制因子2(LATS2)和血管生成素样2(AMOTL2)的表达。VGLL3在恶性乳腺肿瘤细胞和骨肉瘤细胞中高表达，VGLL3基因敲除使YAP和TAZ的核定位增加。LATS2或AMOTL2的敲除以及VGLL3的敲除抑制了乳腺肿瘤细胞的增殖。综上所述，这些结果表明，VGLL3和Teads通过LATS2和AMOTL2激活Hippo途径，导致YAP/TAZ失活，从而促进细胞增殖。
Vestigial-like 3 (VGLL3) is a member of the VGLL family, whose members serve as cofactors for TEA domain?containing transcription factors (TEADs). TEADs promote tissue and tumor development together with the cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Although VGLL3 is involved in tumor cell proliferation, its relationship with TEADs and YAP/TAZ remains largely unknown. To close this research gap, here we established tumor cells stably expressing VGLL3 and found that they exhibit enhanced proliferation. Notably, YAP and TAZ were inactivated in the VGLL3-expressing cells, coinciding with activation of the Hippo pathway, which suppresses YAP/TAZ activities. VGLL3 in combination with TEADs promoted expression of the Hippo pathway components large tumor suppressor kinase (LATS2) and angiomotin-like 2 (AMOTL2). VGLL3 was highly expressed in malignant breast tumor cells and osteosarcoma cells, and VGLL3 knockdown increased nuclear localization of YAP and TAZ. Knockdown of LATS2 or AMOTL2, as well as VGLL3 knockdown, repressed proliferation of breast tumor cells. Together, these results suggest that VGLL3 together with TEADs promotes cell proliferation by activating the Hippo pathway through LATS2 and AMOTL2, leading to YAP/TAZ inactivation.