Abstract
Loss of the cell polarity gene could cooperate with oncogenic Ras to drive tumor growth and invasion, which critically depends on the c-Jun N-terminal Kinase (JNK) signaling pathway in Drosophila. By performing a genetic screen, we have identified Src42A, the ortholog of mammalian Src, as a key modulator of both RasV12/lgl−/− triggered tumor invasion and loss of cell polarity gene-induced cell migration. Our genetic study further demonstrated that the Bendless (Ben)/dUev1a ubiquitin E2 complex is an essential regulator of Src42A-induced, JNK-mediated cell migration. Furthermore, we showed that ectopic Ben/dUev1a expression induced invasive cell migration along with increased MMP1 production in wing disc epithelia. Moreover, Ben/dUev1a could cooperate with RasV12 to promote tumor overgrowth and invasion. In addition, we found that the Ben/dUev1a complex is required for ectopic Src42A-triggered cell death and endogenous Src42A-dependent thorax closure. Our data not only provide a mechanistic insight into the role of Src in development and disease but also propose a potential oncogenic function for Ubc13 and Uev1a, the mammalian homologs of Ben and dUev1a.
Highlights
The c-Jun N-terminal Kinase (JNK) pathway is evolutionarily conserved from fly to human and has an essential role in regulating a wide range of cellular activities including proliferation, differentiation, migration and apoptosis.[15]
Consistent with the well-documented role of Src family kinases in promoting mammalian tumor invasion,[28] Cagan and colleagues found that inhibition of C-terminal SRC kinase (Csk), a negative regulator of Src family kinases, triggered JNK signaling-mediated cell invasion in Drosophila wing discs.[13]
Co-expression of oncogenic Ras (RasV12) in lgl-mutant cells in eye–antenna discs using the ey-FLP/MARCM system induces strong tumor-like growths (Figure 1a), with invasive migration into the ventral nerve cord (VNC) 8 days after egg laying (AEL) (Figure 1a0).[10,16,29]
Summary
The c-Jun N-terminal Kinase (JNK) pathway is evolutionarily conserved from fly to human and has an essential role in regulating a wide range of cellular activities including proliferation, differentiation, migration and apoptosis.[15]. JNK signaling has been shown to have an important role in modulating RasV12/scrib À / À -triggered tumor growth and metastasis, as well as RafGOF/RhoGEF2-induced tumorgenesis.[14,16,17]. Src42A and Src64B have a redundant role in regulating dorsal closure and are both required for tracheal cell morphogenesis.[24,25] Recent studies found that Src64B could induce JNK-dependent overgrowth and expression of Yorkie’s (Yki) target genes when cell death was blocked by expressing p35.26 When. Src64B was overexpressed in a clone context, it induced non-autonomous tumor overgrowth through JNK-dependent propagation of Yki activity.[27] Consistent with the well-documented role of Src family kinases in promoting mammalian tumor invasion,[28] Cagan and colleagues found that inhibition of Csk, a negative regulator of Src family kinases, triggered JNK signaling-mediated cell invasion in Drosophila wing discs.[13]. A direct involvement of Src in tumor metastasis and cell invasion, and its underlying mechanisms, remain largely elusive
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
