Kwon Hailey J, Waghmare Indrayani, Verghese Shilpi, Singh Aditi, Singh Amit, Kango-Singh Madhuri
Department of Biology, University of Dayton, Dayton, OH 45469, USA.
Centerville High School, Centerville, OH 45459, USA.
Dev Biol. 2015 Jan 1;397(1):67-76. doi: 10.1016/j.ydbio.2014.10.010. Epub 2014 Oct 22.
The Hippo signaling pathway is involved in regulating tissue size by inhibiting cell proliferation and promoting apoptosis. Aberrant Hippo pathway function is often detected in human cancers and correlates with poor prognosis. The Drosophila C-terminal Src kinase (d-Csk) is a genetic modifier of warts (wts), a tumor-suppressor gene in the Hippo pathway, and interacts with the Src oncogene. Reduction in d-Csk expression and the consequent activation of Src are frequently seen in several cancers including hepatocellular and colorectal tumors. Previous studies show that d-Csk regulates cell proliferation and tissue size during development. Given the similarity in the loss-of-function phenotypes of d-Csk and wts, we have investigated the interactions of d-Csk with the Hippo pathway. Here we present multiple lines of evidence suggesting that d-Csk regulates growth via the Hippo signaling pathway. We show that loss of dCsk caused increased Yki activity, and our genetic epistasis places dCsk downstream of Dachs. Furthermore, dCsk requires Yki for its growth regulatory functions, suggesting that dCsk is another upstream member of the network of genes that interact to regulate Wts and its effector Yki in the Hippo signaling pathway.
河马信号通路通过抑制细胞增殖和促进细胞凋亡参与调节组织大小。在人类癌症中经常检测到异常的河马信号通路功能，且与预后不良相关。果蝇C末端Src激酶（d-Csk）是河马信号通路中肿瘤抑制基因warts（wts）的遗传修饰因子，并与Src癌基因相互作用。在包括肝细胞癌和结肠直肠癌在内的几种癌症中，经常可见d-Csk表达降低以及随之而来的Src激活。先前的研究表明，d-Csk在发育过程中调节细胞增殖和组织大小。鉴于d-Csk和wts功能丧失表型的相似性，我们研究了d-Csk与河马信号通路的相互作用。在此，我们提供多条证据表明d-Csk通过河马信号通路调节生长。我们发现dCsk缺失导致Yki活性增加，并且我们的遗传上位分析表明dCsk位于Dachs下游。此外，dCsk的生长调节功能需要Yki，这表明dCsk是河马信号通路中与Wts及其效应因子Yki相互作用以进行调节的基因网络的另一个上游成员。
