Recruitment of JNK to JIP1 and JNK-dependent JIP1 Phosphorylation Regulates JNK Module Dynamics and Activation

Abstract

Mitogen-activated protein kinases (MAPKs)1 link a variety of extracellular signals to a diverse range of cellular responses such as proliferation, differentiation, and apoptosis. Three groups of mammalian MAPKs and the upstream kinases and stimuli that activate them have been studied most extensively. These include the p42/p44 MAPK (extracellular signal-regulated kinases, ERK1 and -2), that are generally activated by mitogens and differentiation-inducing stimuli, the stress-activated protein kinases (p46/p54 SAPK or JNK1, 2, or 3 and their splice isoforms) and the p38 mapk (1-6). The stress-activated protein kinases have also been termed JNK protein kinases because they were identified as the principal c-Jun N-terminal kinases. The JNK family kinases are activated by cell stress-inducing stimuli such as heat shock, UV irradiation, hyperosmolarity, and ischemia/reperfusion injury, and by activation of specific cell surface receptors (7-9). Studies performed in cell culture systems and investigation of genetic mutants in a number of model organisms has begun to establish a variety of distinct physiological roles for individual stress-activated protein kinases and their associated pathways. Indeed, distinct JNK family kinases have been implicated in multiple specific biological processes that include but are not limited to embryonic morphogenesis, regulation of the apoptotic response to cellular injury, regulation of thymocyte development and activation, and regulation of proliferation (10 -17).Experiments in yeast have provided evidence that MAP kinase pathways are assembled from a unique combination of protein kinases into distinct protein complexes or modules (18,19). The minimal MAPK module uniformly contains a MAP-KKK, a MAPKK, and a MAPK. The components of these modules interact via direct protein-protein interactions and/or are tethered to scaffolding proteins (20 -25). Importantly, assembly of MAPK modules appears to allow segregation of MAPK signaling components into units that are responsive to independent stimuli, that obtain appropriate subcellular targeting, that are insulated from similar modules, and that can regulate functionally distinct substrates (26 -28). Identification of the JIP family of JNK scaffolding proteins first established that mammalian cells organize JNK pathways into modules in a fashion similar to yeast (29). Three JIP family genes and several splice isoforms have been identified (30 -32). JIP proteins can form homo-and hetero-oligomers and are phosphoproteins. Whereas JIP3 is structurally distant from JIP1 and JIP2, each has been demonstrated to associate directly with a mixed lineage kinase, with MKK7 and with JNK (29,31,33). It has been proposed that JIP proteins facilitate mixed lineage kinase-dependent signal transduction to JNK possibly by aggregating the three components of a JNK module (30).Although a considerable amount of work has been done to establish the role of JIP1 in regulating JNK signaling, less is known about the mechanisms that govern this regulation. We previou...

Inhibition of membrane depolarisation-induced transcriptional activity of cyclic AMP response element binding protein (CREB) by the dual-leucine-zipper-bearing kinase in a pancreatic islet beta cell line

“…Cterminal of the kinase domain DLK has two leucine zipper motifs that mediate protein dimerisation by forming coiledcoil structures [18]. However, within the cell and under basal conditions, DLK is associated with the scaffold proteins JNK interacting protein (JIP) [34][35][36] and Plenty of SH3 [36], which assemble and facilitate the activation of the DLK-dependent JNK module. JIP maintains DLK in a monomeric, unphosphorylated, inactive state [35,36].…”

“…However, within the cell and under basal conditions, DLK is associated with the scaffold proteins JNK interacting protein (JIP) [34][35][36] and Plenty of SH3 [36], which assemble and facilitate the activation of the DLK-dependent JNK module. JIP maintains DLK in a monomeric, unphosphorylated, inactive state [35,36]. It is assumed that signals promoting the dissociation of DLK from JIP lead to homodimerisation of DLK via its leucine zipper domains, followed by its autophosphorylation and activation [35][36][37].…”

“…JIP maintains DLK in a monomeric, unphosphorylated, inactive state [35,36]. It is assumed that signals promoting the dissociation of DLK from JIP lead to homodimerisation of DLK via its leucine zipper domains, followed by its autophosphorylation and activation [35][36][37]. Thus the overexpression of DLK also results in its activation [34].…”

Down-regulation of the Mixed-lineage Dual Leucine Zipper-bearing Kinase by Heat Shock Protein 70 and Its Co-chaperone CHIP

“…Work from a number of laboratories has also established that the regulation of DLK involves heterologous interactions with scaffolding and inhibitory proteins. The binding of DLK to these proteins, in particular JNK-interacting protein (JIP)-1 and MAPK upstream kinase (MUK)-binding inhibitory protein (MBIP), is likely to play an important role in DLK regulation by preventing its dimerization (21)(22)(23). Another important mechanism by which DLK is proposed to be regulated is through changes in its phosphorylation status.…”

Loss of TRB3 Alters Dynamics of MLK3-JNK Signaling and Inhibits Cytokine-activated Pancreatic Beta Cell Death

“…We have reported that TRAF6-mediated, Lys-63-linked ubiquitination induces MLK3 dissociation from JIP1 scaffold, enabling its dimerization and activation of the MLK3-JNK cascade (14). Furthermore, JNK activation is sustained by direct phosphorylation of JIP1, which inhibits re-association of MAP3Ks with JIP1 (53). Notably, Xu et al (18) have demonstrated that upon cytokine treatment, each component of the JNK activation cascade contributes to the mutual stabilization of the entire module sustaining a feed-forward loop of MLK3-MKK7 and JNK activation.…”