Drosophila C-terminal Src kinase regulates growth via the Hippo signaling pathway

Abstract

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.

αE-catenin inhibits a Src–YAP1 oncogenic module that couples tyrosine kinases and the effector of Hippo signaling pathway

“…This pathway is activated in confluent cells, where it suppresses YAP1 nuclear localization and thereby inhibits its transcriptional activity (Zhao et al 2007). It had been demonstrated previously that SRC and other SFKs can positively (Shanzer et al 2015) and negatively regulate canonical Hippo signaling pathway (Enomoto and Igaki 2013;Pijuan-Galito et al 2014;Kim and Gumbiner 2015;Kwon et al 2015). In accordance with these findings, we observed negative regulation of S127 YAP1 phosphorylation in sparse keratinocytes (Supplemental Fig.…”

“…It has been reported that CA-SRC can negatively regulate the canonical Hippo signaling pathway (Enomoto and Igaki 2013;Kim and Gumbiner 2015;Kwon et al 2015). To determine whether CA-SRC regulates YAP1 activity in keratinocytes via the canonical Hippo signaling pathway, we performed luciferase assays with the YAP1-regulated reporter in cells with knockdown of endogenous LATS1/2 (Fig.…”

The Hippo pathway effector Yki downregulates Wg signaling to promote retinal differentiation in the Drosophila eye

“…The fly stocks used were UAS-fat RNAi (Dietzl et al, 2007), UAS-wts RNAi (Fernandez et al, 2011;Rauskolb et al, 2011), UAS-yki RNAi(N+C) (Zhang et al, 2008), UAS-D (Mao et al, 2006), UAS-hpo (Udan et al, 2003), UAS-wts 13F (Kwon et al, 2015), y w; hsFLP; UAS-hpo RNAisymp19 / SM6-TM6B, Tb (Pantalacci et al, 2003), dpp-Gal4 (Staehling-Hampton et al, 1994), bi-Gal4 (Calleja et al, 1996), UAS-Dicer (Misquitta et al, 2008), dpp-lacZ (Blackman et al, 1991), UAS-Sgg (Hazelett et al, 1998), UAS-dTCF DN5 (van de Wetering et al, 1991), w; P(Act>y + >Gal4)25 P(UAS-GFP S65T )/CyO (Ito et al, 1997), y w hsFLP 122 (Struhl and Basler, 1993), w; wts x1 FRT82B/TM6B, Tb (Xu et al, 1995) and Canton-S. For activation of Yki, we used the following transgenes: UAS-yki GFP (full length) (Oh and Irvine, 2008), UASyki S168A (Oh and Irvine, 2008) and UAS-yki 3SA (Oh and Irvine, 2008). We used the Gal4/UAS system for targeted misexpression studies (Brand and Perrimon, 1993).…”

Csk regulates angiotensin II-induced podocyte apoptosis

“…Interestingly, the substrates of Csk are anchored in the cell membrane. Csk suppression of SFK activity involves the movement of Csk to the SFK locations [25][26][27]. During this process, Csk efficiently binds to scaffolding/adapter proteins (Cbp/PAG, paxillin, JAM-A, Caveolin-1) located in membranes that are enriched with cholesterol.…”

“…Jo et al [31] found that H 2 O 2 induces Caveolin-1 and Csk complex formation in CRT-MG cells. Kwon et al [26] showed that Csk regulates growth via the Hippo signaling pathway in Drosophila. These results support our finding that Csk is involved in cell apoptosis.…”