A Drosophila TNF-receptor-associated factor (TRAF) binds the Ste20 kinase Misshapen and activates Jun kinase

Abstract

Two families of protein kinases that are closely related to Ste20 in their kinase domain have been identified - the p21-activated protein kinase (Pak) and SPS1 families [1-3]. In contrast to Pak family members, SPS1 family members do not bind and are not activated by GTP-bound p21Rac and Cdc42. We recently placed a member of the SPS1 family, called Misshapen (Msn), genetically upstream of the c-Jun amino-terminal (JNK) mitogen-activated protein (MAP) kinase module in Drosophila [4]. The failure to activate JNK in Drosophila leads to embryonic lethality due to the failure of these embryos to stimulate dorsal closure [5-8]. Msn probably functions as a MAP kinase kinase kinase kinase in Drosophila, activating the JNK pathway via an, as yet, undefined MAP kinase kinase kinase. We have identified a Drosophila TNF-receptor-associated factor, DTRAF1, by screening for Msn-interacting proteins using the yeast two-hybrid system. In contrast to the mammalian TRAFs that have been shown to activate JNK, DTRAF1 lacks an amino-terminal 'Ring-finger' domain, and overexpression of a truncated DTRAF1, consisting of only its TRAF domain, activates JNK. We also identified another DTRAF, DTRAF2, that contains an amino-terminal Ring-finger domain. Msn specifically binds the TRAF domain of DTRAF1 but not that of DTRAF2. In Drosophila, DTRAF1 is thus a good candidate for an upstream molecule that regulates the JNK pathway by interacting with, and activating, Msn. Consistent with this idea, expression of a dominant-negative Msn mutant protein blocks the activation of JNK by DTRAF1. Furthermore, coexpression of Msn with DTRAF1 leads to the synergistic activation of JNK. We have extended some of these observations to the mammalian homolog of Msn, Nck-interacting kinase (NIK), suggesting that TRAFs also play a critical role in regulating Ste20 kinases in mammals.

The Nonmuscle Myosin Phosphatase PP1β (flapwing) Negatively Regulates Jun N-Terminal Kinase in Wing Imaginal Discs of Drosophila

“…Several mechanisms have been identified that activate JNK and induce apoptosis in wing imaginal discs. For example, mutations in the caspase inhibitor DTraf1 (Drosophila tumor necrosis factor receptor-associated factor 1), as well as inhibition of DTraf1 by overexpression of Hid (head involution defective), Rpr (reaper), or Grim, induces JNK-mediated apoptosis Ryoo 2004), possibly through Msn (misshapen) or Ask1 (apoptosis signal-regulating kinase 1) (Liu 1999;. Other factors involved in inducing apoptosis and activating JNK are Eiger (Drosophila tumor-necrosis factor superfamily ligand) , its receptor Wengen (Kauppila 2003), Src42A (Tateno 2000), the serine C-palmitoyltransferase Lace (Adachi-Yamada et al 1999b), Blistery (Drosophila Tensin) (Lee et al 2003), and Decapentaplegic and Wingless (AdachiYamada et al 1999a).…”

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

“…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). While the main signaling pathway transmits from MSN to JNK hierarchically, other factors connected to this main pathway also function in fine-tuning of the signaling, especially in activating or repressing the JNK activity (Chen et al, 2002;Neisch et al, 2010;Shanley et al, 2001;Yang et al, 1997).…”

High levels of dRYBP induce apoptosis in Drosophila imaginal cells through the activation of reaper and the requirement of trithorax, dredd and dFADD

“…The Drosophila TNF/TNFR homologs are EIGER/WENGEN [9,10]. Three Drosophila members of the TRAF family have been identified [11,12]. The Drosophila homologs of the DED (Death Domain)-containing protein FADD and caspase-8 are dFADD and DREDD, respectively [13,14].…”