cdc37 is essential for JNK pathway activation and wound closure in Drosophila

Abstract

Wound closure in the Drosophila larval epidermis mainly involves nonproliferative, endocyling epithelial cells. Consequently, it is largely mediated by cell growth and migration. We discovered that both cell growth and migration in Drosophila require the cochaperone-encoding gene cdc37. Larvae lacking cdc37 in the epidermis failed to close wounds, and the cells of the epidermis failed to change cell shape and polarize. Likewise, wound-induced cell growth was significantly reduced, and correlated with a reduction in the size of the cell nucleus. The c-Jun N-terminal kinase (JNK) pathway, which is essential for wound closure, was not typically activated in injured cdc37 knockdown larvae. In addition, JNK, Hep, Mkk4, and Tak1 protein levels were reduced, consistent with previous reports showing that Cdc37 is important for the stability of various client kinases. Protein levels of the integrin β subunit and its wound-induced protein expression were also reduced, reflecting the disruption of JNK activation, which is crucial for expression of integrin β during wound closure. These results are consistent with a role of Cdc37 in maintaining the stability of the JNK pathway kinases, thus mediating cell growth and migration during Drosophila wound healing.

AI reveals a damage signalling hierarchy that coordinates different cell behaviours driving wound re-epithelialisation

“…Next, we disrupted JNK signalling, which is known to be key in developmental morphogenetic episodes such as dorsal closure (Tafesh-Edwards & Eleftherianos, 2020), and in wound healing, both in the formation of actomyosin cables and for associated cell shape changes (Kwon et al, 2010; Lee et al, 2019).…”

Regulation of Mitogen-Activated Protein Kinase Signaling Pathways by the Ubiquitin-Proteasome System and Its Pharmacological Potential

“…Similar to mammals, ubiquitination of TAK1 terminates JNK signaling in the innate immune response. Cdc37 also acts as a molecular chaperone for TAK1 in Drosophila, as knockdown of Cdc37 in larvae induces a decrease in TAK1 protein abundance (Lee et al, 2019).…”

Pvr and distinct downstream signaling factors are required for hemocyte spreading and epidermal wound closure at Drosophila larval wound sites

“…Following injury, larval barrier epithelial cells at the wound edge locally detach from the apical cuticle and migrate into the wound gap. This process requires both JNK signaling ( Galko and Krasnow 2004 ; Lesch et al 2010 ; Lee et al 2019 ) and Pvr signaling ( Wu et al 2009 ). The latter is required in some manner for epithelial extension into the wound site, though it has been difficult to identify downstream genes of this pathway given a lack of pathway reporters that function well in vivo during the larval stage.…”