Activation of the JNK pathway during dorsal closure in Drosophila requires the mixed lineage kinase, slipper

Abstract

The Jun kinase (JNK) pathway has been characterized for its role in stimulating AP-1 activity and for modulating the balance between cell growth and death during development, inflammation, and cancer. Six families of mammalian kinases acting at the level of JNKKK have emerged as upstream regulators of JNK activity (MLK, LZK, TAK, ASK, MEKK, and TPL); however, the specificity underlying which kinase is utilized for transducing a distinct signal is poorly understood. In Drosophila, JNK signaling plays a central role in dorsal closure, controlling cell fate and cell sheet morphogenesis during embryogenesis. Notably, in the fly genome, there are single homologs of each of the mammalian JNKKK families. Here, we identify mutations in one of those, a mixed lineage kinase, named slipper (slpr), and show that it is required for JNK activation during dorsal closure. Furthermore, our results show that other putative JNKKKs cannot compensate for the loss of slpr function and, thus, may regulate other JNK or MAPK-dependent processes.

Role of Rho family GTPases in epithelial morphogenesis

“…These include DJNKK (Hemipterous; Hep) (Glise et al 1995), which subsequently activates DJNK (Basket; Bsk) (Sluss et al 1996;Glise and Noselli 1997). In addition, the Ste20-related kinase, Misshapen (Msn) has been shown to function upstream of Hep and Bsk to stimulate dorsal closure (Su et al 1998), and more recently, Stronach and Perrimon (2002) have identified Slipper (Slpr) as the upstream activator of DJNKK required for dorsal closure. A model is proposed that Msn, Slpr, and DRac1 participate in a ternary signaling complex to stimulate DJNK signal transduction (Stronach and Perrimon 2002).…”

“…Finally, the leading edges of both sides meet at the dorsal midline and fuse ( Fig. 3B; for reviews, see Knust 1997;Goberdhan and Wilson 1998;Noselli 1998;Stronach and Perrimon 1999).…”

“…3C) (for review, see Stronach and Perrimon 1999). These include DJNKK (Hemipterous; Hep) (Glise et al 1995), which subsequently activates DJNK (Basket; Bsk) (Sluss et al 1996;Glise and Noselli 1997).…”

“…In C. elegans, the enclosure of the ventral surface of the embryo involves a two-step process in which two functionally distinct groups of hypodermal cells meet and fuse to seal the ventral midline; one is accompanied by filopodia for-mation and the other by purse-string contraction (Williams-Masson et al 1997;Simske and Hardin 2001). During Drosophila embryogenesis, the epidermis undergoes a morphogenetic movement, termed dorsal closure (DC), to establish the dorsal ectoderm (Knust 1997;Goberdhan and Wilson 1998;Noselli 1998;Stronach and Perrimon 1999). Similar to the mechanism described for reepithalization of embryonic skin and some tissue culture wounds, one of the major forces that drives the movement of the epithelial sheets in the Drosophila embryo is the contraction of a cable of actin and myosin running around the circumference of the leading epithelial margin (see below).…”

Drosophila Smt3 negatively regulates JNK signaling through sequestering Hipk in the nucleus

“…In Drosophila, JNK is encoded by the gene basket (bsk). The upstream regulators of Bsk include a series of kinases that form a signaling cascade (Stronach and Perrimon, 2002;Takatsu et al, 2000;Tateno et al, 2000;Xue et al, 2007). MSN, a MAPK kinase kinase kinase (MAPKKKK) receives signals from cell surface receptors and initiates this signaling cascade (Liu et al, 1999;Xue et al, 2007).…”