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. 2013 Jan;14(1):65-72.
doi: 10.1038/embor.2012.185. Epub 2012 Nov 30.

Src controls tumorigenesis via JNK-dependent regulation of the Hippo pathway in Drosophila

Masato Enomoto  1 , Tatsushi Igaki
Affiliations

Src controls tumorigenesis via JNK-dependent regulation of the Hippo pathway in Drosophila

Masato Enomoto et al. EMBO Rep. 2013 Jan.

Abstract

Cell-cell interactions within the tumour microenvironment have crucial roles in epithelial tumorigenesis. Using Drosophila genetics, we show that the oncoprotein Src controls tumour microenvironment by Jun N-terminal kinase (JNK)-dependent regulation of the Hippo pathway. Clones of cells with elevated Src expression activate the Rac-Diaphanous and Ras-mitogen-activated protein kinase (MAPK) pathways, which cooperatively induce F-actin accumulation, thereby leading to activation of the Hippo pathway effector Yorkie (Yki). Simultaneously, Src activates the JNK pathway, which antagonizes the autonomous Yki activity and causes propagation of Yki activity to neighbouring cells, resulting in the overgrowth of surrounding tissue. Our data provide a mechanism to explain how oncogenic mutations regulate tumour microenvironment through cell-cell communication.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Src causes non-autonomous tissue overgrowth. (A–D) Eye-antennal discs (A, A′, C and C′) and eyes (B, B′, D and D′) of adult flies bearing GFP-labelled wild-type (A, A′, B and B′) or Src64B-expressing (C, C′, D and D′) clones are shown. Cell nuclei were stained with DAPI (blue) (A′ and C′). Clones were visualized by GFP fluorescence in the adult (B′,D′). See supplementary Information online for genotypes. DAPI, 4,6-diamidino-2-phenylindole; GFP, green fluorescent protein; wt, wild type.
Figure 2
Figure 2
Src induces autonomous and non-autonomous activation of Yki. (A–F) Eye-antennal discs (A–A′′′′′′, Bld–B′′′′′′, C–C′′′′ and E–E′′′′) and eyes (D, D′, F and F′) of adult flies bearing GFP-labelled MARCM clones expressing Src64B in diap1-lacZ/+ background (A–A′′′′′′), Src64B in ex-lacZ/+ background (B–B′′′′′′), Src64B in yki/+ background (C–C′′′′, D and D′) and Src64B+yki-RNAi (E–E′′′′, F and F′) are shown. The reporter activity was visualized by anti-β-galactosidase staining. (A′′′′)–(A′′′′′′), (B′′′′)–(B′′′′′′), (C′′′), (C′′′′), (E′′′) and (E′′′′) are high-magnification images of the boxed area in (A′′), (B′′), (C′′) and (E′′). Arrows indicate Src64B-expressing clones with lower Yki-target gene expression compared with neighbouring wild-type cells. Cell nuclei were stained with DAPI (blue) (A′′′, B′′′, A′′′′′′ and B′′′′′′). Clones were visualized by GFP fluorescence in the adult (D′ and F′). See supplementary Information online for genotypes. DAPI, 4,6-diamidino-2-phenylindole; GFP, green fluorescent protein.
Figure 3
Figure 3
JNK signalling causes propagation of Yki activity to neighbouring cells. (A–D) Eye-antennal discs bearing GFP-labelled MARCM clones expressing Src64B (A–A′′′′′ and B–B′′′′′) and Src64B+BskDN (C–C′′′′′ and D–D′′′′′) are shown. Caspase activity (A), JNK activity (B) or Yki activity (C and D) was visualized by anti-caspase-3 antibody staining (A), the puc-lacZ reporter (B), the diap1-lacZ reporter (C) or the ex-lacZ reporter (D). (A′′′′)–(D′′′′) and (A′′′′′)–(D′′′′′) are high-magnification images of the boxed area in (A′′)–(D′′). Cell nuclei were stained with DAPI (blue) (A′′′–D′′′). See supplementary Information online for genotypes. DAPI, 4,6-diamidino-2-phenylindole; GFP, green fluorescent protein.
Figure 4
Figure 4
Src activates Yki through F-actin reorganization. (A–J) Eye-antennal discs (A–A′′, B–B′′, C–C′′′, E–E′′′, G–G′′′ and I–I′′′) and eyes (D, D′, F, F′, H, H′, J and J′) of adult flies bearing GFP-labelled MARCM clones expressing Src64B (A–A′′), DiaCA (B–B′′, F and F′), Src64B/dia−/− in diap1-lacZ/+ background (C–C′′′), Src64B/dia−/− (D and D′), DiaCA in diap1-lacZ/+ background (E–E′′′), Src64B+RafDN in diap1-lacZ/+ background (G–G′′′), Src64B+RafDN (H and H′) and DiaCA+RasCA+Eiger in diap1-lacZ/+ background (I–I′′′, J and J′) are shown. F-actin (A, B), or Yki activity (C, E, G and I) was visualized by phalloidin staining (A,B) or the diap1-lacZ reporter (C, E, G and I). C′′, C′′′, E′′, E′′′, G′′, G′′′, I′′ and I′′′ are high-magnification images of the boxed area in C, E, G and I. Clones were visualized by GFP fluorescence in the adult (D′, F′, H′ and J′). See supplementary Information online for genotypes. GFP, green fluorescent protein.
Figure 5
Figure 5
A model for Src-induced tumorigenesis by JNK-dependent Hippo pathway regulation. A cell with elevated Src expression activates the Rac-Dia and the Ras-MAPK pathways, which cooperate to cause Yki activation through the Hippo pathway. At the same time, Src activates JNK signalling that causes propagation of Yki activity to neighbouring cells (left, non-autonomous growth). Blocking JNK signalling in a Src-expressing cell cancels the propagation of Yki activity and leads to autonomous activation of Yki (right, autonomous growth). See text for details. MAPK, mitogen-activated protein kinase.
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