Src Cooperates with Oncogenic Ras in Tumourigenesis via the JNK and PI3K Pathways in Drosophila epithelial Tissue.

Carole L.C Poon,Anthony M Brumby,Helena E Richardson

doi:10.3390/ijms19061585

Carole L.C Poon, Anthony M Brumby + Show 1 more

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https://doi.org/10.3390/ijms19061585

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The Ras oncogene (Rat Sarcoma oncogene, a small GTPase) is a key driver of human cancer, however alone it is insufficient to produce malignancy, due to the induction of cell cycle arrest or senescence. In a Drosophila melanogaster genetic screen for genes that cooperate with oncogenic Ras (bearing the RasV12 mutation, or RasACT), we identified the Drosophila Src (Sarcoma virus oncogene) family non-receptor tyrosine protein kinase genes, Src42A and Src64B, as promoting increased hyperplasia in a whole epithelial tissue context in the Drosophila eye. Moreover, overexpression of Src cooperated with RasACT in epithelial cell clones to drive neoplastic tumourigenesis. We found that Src overexpression alone activated the Jun N-terminal Kinase (JNK) signalling pathway to promote actin cytoskeletal and cell polarity defects and drive apoptosis, whereas, in cooperation with RasACT, JNK led to a loss of differentiation and an invasive phenotype. Src + RasACT cooperative tumourigenesis was dependent on JNK as well as Phosphoinositide 3-Kinase (PI3K) signalling, suggesting that targeting these pathways might provide novel therapeutic opportunities in cancers dependent on Src and Ras signalling.

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IntroductionThe Src (Sarcoma virus oncogene) family of non-receptor tyrosine protein kinases are highly conserved and comprise nine members in vertebrates: Src, Fyn (oncogene related to Src, Fgr, Yes), Yes (Yamaguchi sarcoma virus oncogene), Blk (B Lymphoid Tyrosine Kinase), Yrk (Yes-related kinase), Fgr, Hck (hemopoietic cell kinase), Lck (lymphocyte-specific protein tyrosine kinase) and Lyn (v-yes-1 Yamaguchi sarcoma viral related oncogene homolog) [1]
The Src (Sarcoma virus oncogene) family of non-receptor tyrosine protein kinases are highly conserved and comprise nine members in vertebrates: Src, Fyn, Yes (Yamaguchi sarcoma virus oncogene), Blk (B Lymphoid Tyrosine Kinase), Yrk (Yes-related kinase), Fgr, Hck, Lck and Lyn (v-yes-1 Yamaguchi sarcoma viral related oncogene homolog) [1]
We investigated the role of the Drosophila Src kinases in cooperative tumourigenesis with activated Ras (RasV12 or RasACT) in the fly eye epithelium

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Introduction

The Src (Sarcoma virus oncogene) family of non-receptor tyrosine protein kinases are highly conserved and comprise nine members in vertebrates: Src, Fyn (oncogene related to Src, Fgr, Yes), Yes (Yamaguchi sarcoma virus oncogene), Blk (B Lymphoid Tyrosine Kinase), Yrk (Yes-related kinase), Fgr, Hck (hemopoietic cell kinase), Lck (lymphocyte-specific protein tyrosine kinase) and Lyn (v-yes-1 Yamaguchi sarcoma viral related oncogene homolog) [1]. Src, Fyn and Yes are ubiquitously expressed in tissues and the remaining members are restricted to specific cell types [2]. Src family kinases have pleiotropic functions including intracellular signalling, actin remodelling, cell adhesion and apoptosis [1,3,4,5]. Despite extensive analysis in cell culture and mouse models, the precise role of Src kinases during tumourigenesis in vivo is yet to be clearly defined. Other studies indicate that elevated Src activity is due to increased protein expression and increased kinase activity that enhance tyrosine phosphorylation of substrates [6,8,9,10,11,12,13,14,15,16]

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