Blockade of Crk eliminates Yki/YAP-activated tumors via JNK-mediated apoptosis in Drosophila

Sep 21, 2026

Uploaded by Riley

Selective elimination of cancer cells without harming normal tissue is an ideal anticancer strategy. Using a Drosophila in vivo RNAi screen, researchers test targets that suppress malignant growth in RasV12/scrib−/− imaginal epithelium while sparing normal cell growth. Crk knockdown strongly suppresses tumor expansion by inducing JNK-mediated apoptosis and blocks Yorkie/Yki-YAP activity through impaired F-actin accumulation. Yki/YAP inhibition then channels intracellular JNK signaling to drive apoptosis.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Background

Tumor selectivity and the need for target identification

Drosophila as an in vivo platform

YAP/Yki and CRK/CRKL relevance

Methods and screening strategy

RasV12/scrib−/− tumor mosaic model

In vivo RNAi screen design

Key findings

Crk as a selective tumor suppressor

Mechanism: F-actin accumulation, Yki/YAP inhibition, and JNK apoptosis

communications biology Article |
[https://doi.org/10.1038/s42003-024-06897-w](https://doi.org/10.1038/s42003-024-06897-w) | | | --- | --- | | Blockade of Crk eliminates Yki/YAPactivated tumors via JNK-mediated apoptosis in Drosophila
Check for updates | | | Bungo Kakemura & Tatsushi Igaki | | | Selective elimination of cancer cells without causing deleterious effects on normal cells isan ideal anticancer strategy. Here, using Drosophila cancer model, we performed an in vivo RNAi screen for anticancer targets that selectively eliminate tumors without affecting normal tissue growth. In Drosophila imaginal epithelium, clones of cells expressing oncogenic Ras with simultaneous mutations in the cell polarity gene scribble (RasV12/scrib−/−) develop into malignant tumors. We found that knockdown of Crk, the Drosophila ortholog of human CRK (CT10 regulatory kinase) and CRKL (Crk-like) adapter proteins, signiﬁcantly suppresses growth of RasV12/scrib−/ − tumors by inducing c-Jun N-terminal kinase (JNK)-mediated apoptosis, while it does not affect growth of normal epithelium. Mechanistically, Crk inhibition blocks Yorkie (Yki)/YAP activity by impairing F-actin accumulation, an upstream event of Yki/YAP activation in tumors. Inhibition of Yki/YAP in tumors causes intracellular JNK signaling to be used for apoptosis induction. Given that molecules and signaling pathwaysidentiﬁed in Drosophila are highly conserved and activated in human cancers, our ﬁndings would provide a novel, to the best of our knowledge, anti-cancer strategy against YAP-activated cancers. | | | An ideal strategy against cancer is selective elimination of cancer cells without causing deleterious effects on normal cells. One such approach is the inhibition ofsignaling molecule that is speciﬁcally contributing to cancer cell proliferation or survival. It is therefore crucial to identify such speciﬁc target molecules in cancer cells. However, the complexity of using in vivo models of mammalian cancers has hampered the systematic identiﬁcation of target molecules that can manipulate cancer cells.
Drosophila serves as an ideal in vivo platform for identifying molecules that are speciﬁcally required for cancer cell proliferation or survival1–3. The genetic mosaic technique available in Drosophila4 allows us to dissect the signaling network within tumors and identify tumorspeciﬁc proliferation or survival signaling by tumor-speciﬁc genetic manipulations or gene silencing. In Drosophila imaginal epithelia, genetic mosaic clones of cells expressing oncogenic Ras (RasV12) with simultaneous mutations in apico-basal cell polarity gene scribble (scrib) develop into malignant tumors5. TheRasV12/scrib-/-tumors exhibit human cancerlike phenotypes such as tumor overgrowth, invasion, metastasis, and ultimately animal death5–7, providing an ideal genetic model to study tumor growth and progression.
YAP (YES-associated protein 1) is a transcriptional co-activator implicated in cancer initiation, progression, and invasion8. YAP activity is frequently elevated in various types of cancer9 and thus YAP and its | upstream regulatory molecules can be therapeutic targets against cancer10–12. Drosophila possesses theYAP homolog Yorkie(Yki), which functions asan oncogene that enhances cell proliferation and promotes cell survival13. Since the function of YAP and its upstream regulatory molecules are well conserved in Drosophila14, identiﬁcation of molecules that effectively manipulate Yki-activated tumors in Drosophila would provide new strategies against YAP-activated cancers in humans.
Human CRK (CT10 regulatory kinase) and CRKL (CRK-like) are adaptor proteins composed of SH2 and SH3 domains, which regulate various cellular processes such as cell motility, adhesion, and proliferation15, 16. Expression ofCRKorCRKLis elevated in various types of cancers and contributes to tumor growth17, 18. Hence CRK and CRKL have gained attention for their potential as targets for cancer

FAQs

What tumor model was used to identify anticancer targets?

The study used Drosophila imaginal epithelium clones expressing oncogenic Ras with simultaneous mutations in the cell polarity gene scribble (RasV12/scrib−/−) to generate malignant tumors for screening.

How does Crk knockdown affect RasV12/scrib−/− tumors?

Crk knockdown significantly suppresses tumor growth by inducing c-Jun N-terminal kinase (JNK)-mediated apoptosis while not affecting the growth of normal epithelium.

What mechanism links Crk inhibition to apoptosis in tumors?

Crk inhibition blocks Yorkie (Yki)/YAP activity by impairing F-actin accumulation, an upstream step in Yki/YAP activation; Yki/YAP inhibition then enables intracellular JNK signaling to trigger apoptosis.

Sep 21, 2026

Uploaded by Riley