Dual Leucine Zipper-bearing Kinase (DLK) Activates p46SAPK and p38  but Not ERK2

Fan, Guangyao; Merritt, Steven E.; Kortenjann, M; Shaw, Peter E.; Holzman, Lawrence B.

doi:10.1074/jbc.271.40.24788

Cited by 133 publications

(110 citation statements)

References 47 publications

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“…As such, DLK phosphorylates and activates the dualspecificity MAPKK MKK7 and MKK4, which in turn phosphorylate and activate the MAPK JNK [26,33,34]. Cterminal of the kinase domain DLK has two leucine zipper motifs that mediate protein dimerisation by forming coiledcoil structures [18].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2005

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Aims/hypothesis: The activation of the transcription factor cyclic AMP response element binding protein (CREB) by protein kinase A is inhibited by the human orthologue of the mitogen-activated protein kinase, dualleucine-zipper-bearing kinase (DLK) in teratocarcinoma cells. However, pancreatic beta cells are electrically excitable and a major pathway regulating CREB in these cells is membrane depolarisation, leading to calcium influx and activation of the calcium/calmodulin-dependent protein phosphatase calcineurin. Therefore, the effect of DLK on CREB activity induced by membrane depolarisation was investigated in the beta cell line HIT. Materials and methods: Reporter gene assays and biochemical techniques were used. Results: RT-PCR, Western blot analysis and immunohistochemistry demonstrated the expression of DLK in HIT cells and primary mouse islets. In transient transfection experiments, DLK inhibited both GAL4-CREB activity induced by membrane depolarisation, and transcription directed by the CREB binding site, the cyclic AMP response element. Furthermore, DLK inhibited the transcriptional activity conferred by the CREB coactivator, CREB binding protein, both under basal conditions and after membrane depolarisation. DLK was also effective in response to glucose, the most potent physiological stimulus and known to cause membrane depolarisation of beta cells. Inhibition of calcineurin enhanced DLK activity, whereas overexpression of calcineurin reduced the inhibition by DLK of transcription directed by cyclic AMP response element after membrane depolarisation. Conclusions/interpretation: These results demonstrate a calcineurin-sensitive inhibition by DLK of CREB activity after membrane depolarisation in pancreatic islet beta cells. This inhibition may, at least partially, be mediated at the coactivator level. The results thus suggest that DLK plays a role in the regulation of beta cell function, including insulin gene transcription and beta cell apoptosis.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2005

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“…Like all members of the MLK family, DLK acts as a key component of the JNK signaling pathway (1,48). Although significant progress has been achieved in the past few years in our understanding of how DLK regulates the JNK pathway, very little is known about the identity of its physiological agonists and the mechanisms responsible for its own regulation.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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Dual leucine zipper-bearing kinase (DLK) is a mixed-lineage kinase family member that acts as an upstream activator of the c-Jun N-terminal kinases. As opposed to other components of this pathway, very little is currently known regarding the mechanisms by which DLK is regulated in mammalian cells. Here we identify the stress-inducible heat shock protein 70 (Hsp70) as a negative regulator of DLK expression and activity. Support for this notion derives from data showing that Hsp70 induces the proteasomal degradation of DLK when both proteins are coexpressed in COS-7 cells. Hsp70-mediated degradation occurs with expression of wild-type DLK, which functions as a constitutively activated protein in these cells but not kinase-defective DLK. Interestingly, the Hsp70 co-chaperone CHIP, an E3 ubiquitin ligase, seems to be indispensable for this process since Hsp70 failed to induce DLK degradation in COS-7 cells expressing a CHIP mutant unable to catalyze ubiquitination or in immortalized fibroblasts derived from CHIP knock-out mice. Consistent with these data, we have found that endogenous DLK becomes sensitive to CHIP-dependent proteasomal degradation when it is activated by okadaic acid and that down-regulation of Hsp70 levels with an Hsp70 antisense attenuates this sensitivity. Therefore, our studies suggest that Hsp70 contributes to the regulation of activated DLK by promoting its CHIPdependent proteasomal degradation.Dual leucine zipper-bearing kinase (DLK) 2 is a serine/threonine kinase that belongs to a family of mitogen-activated protein kinase kinase kinases, known as mixed-lineage kinases (MLKs) (1). Members of this family, which also include MLK1, MLK2, MLK3, MLK4, leucine zipper-bearing kinase, and leucine zipper and sterile ␣-motif kinase (1), are characterized at the structural level by the presence of a catalytic domain bearing amino acid motifs found in serine/threonine and tyrosine kinases and one or two leucine zipper motifs, which regulate their activity by mediating protein dimerization or oligomerization (2-5). A number of other interesting motifs that are likely important for protein binding have also been identified in specific members of the MLK family. For instance, MLK2 and MLK3 contain a Src homology 3 (SH3) domain in their N-terminal region that binds, respectively, the GTPase dynamin and the Ste20-related protein kinase HPK1 (6, 7). Both MLK proteins also possess a functional Cdc42/Rac interactive binding (CRIB) motif that mediates association with Cdc42 and Rac1 in a GTP-dependent manner (8, 9).The importance of the MLKs as signaling molecules is highlighted by the fact that these proteins act as key regulators of the c-Jun N-terminal kinase (JNK) subgroup of mitogen-activated protein kinases (1). Specifically, all MLK family members regulate the JNK pathway by phosphorylating and activating the JNK direct upstream activators . In addition to their role in catalyzing JNK activation, MLKs are also known to contribute to apoptosis in neuronal cells. Indeed, when dominant negative forms of MLKs...

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“…The small GTPbinding proteins act via various, multiple downstream mitogenactivated protein (MAP) kinase kinase kinases, depending on the cell type, which bind the active GTP-bound form of the small G-proteins and induce JNK activity and transcriptional activation (Lim et al, 1996;Tapon and Hall, 1997;Van Aelst and D'Souza-Schorey, 1997) (for review, see Johnson, 1999). There are several likely intermediates in the signaling cascades linking Cdc42 to the JNK pathway, including the p21-activated kinases (rat p65PAK/PAK1/PAK ␣, PAK-2/PAK ␥, PAK-3/PAK ␤, and PAK4; Bagrodia et al, 1995;Knaus et al, 1995;Manser et al, 1995;Martin et al, 1995;Brown et al, 1996;Abo et al, 1998), the germinal center kinase (GCK; Pombo et al, 1995), the nickinteracting protein (NIK; Su et al, 1997), MEKK1 and MEKK4 (Fanger et al, 1997;Gerwins et al, 1997), plenty of SH3 (POSH) (Tapon et al, 1998), and the mixed lineage kinase family (MLK1, MLK2, MLK3, DLK, LZK) (Dorow et al, 1993;Holzman et al, 1994;Reddy and Pleasure, 1994;Fan et al, 1996;Hirai et al, 1996;Rana et al, 1996;Teramoto et al, 1996;Tibbles et al, 1996;Hirai et al, 1997;Sakuma et al, 1997;Nagata et al, 1998).…”

Section: Abstract: Apoptosis; Cdc42; Mlk3; Signal Transduction; Sympmentioning

confidence: 99%

Evidence for a Role of Mixed Lineage Kinases in Neuronal Apoptosis

et al. 2001

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Superior cervical ganglion (SCG) sympathetic neurons die by apoptosis when deprived of nerve growth factor (NGF). It has been shown previously that the induction of apoptosis in these neurons at NGF withdrawal requires both the activity of the small GTP-binding protein Cdc42 and the activation of the c-Jun N-terminal kinase (JNK) pathway. The mixed lineage kinase 3 (MLK3) belongs to a family of mitogen-activated protein (MAP) kinase kinase kinases. MLK3 contains a Cdc42/Rac interactive-binding (CRIB) domain and activates both the JNK and the p38 MAP kinase pathways. In this study the role of MLK3 in the induction of apoptosis in sympathetic neurons has been investigated. Overexpression of an active MLK3 induces activation of the JNK pathway and apoptosis in SCG neurons. In addition, overexpression of kinase dead mutants of MLK3 blocks apoptosis as well as c-Jun phosphorylation induced by NGF deprivation. More importantly, MLK3 activity seems to increase by 5 hr after NGF withdrawal in both differentiated PC12 cells and SCG neurons. We also show that MLK3 lies downstream of Cdc42 in the neuronal death pathway. Regulation of MLK3 in neurons seems to be dependent on MLK3 activity and possibly on an additional cellular component, but not on its binding to Cdc42. These results suggest that MLK3, or a closely related kinase, is a physiological element of NGF withdrawal-induced activation of the Cdc42-c-Jun pathway and neuronal death. MLK3 therefore could be an interesting therapeutic target in a number of neurodegenerative diseases involving neuronal apoptosis. Key words: apoptosis; Cdc42; MLK3; signal transduction; sympathetic neurons; Jun kinaseActivation of the c-Jun transcriptional pathway has been shown to be an important regulator of apoptosis of sympathetic neurons induced by nerve growth factor (NGF) withdrawal by both microinjection of antibodies against c-Jun or expression of a c-Jun dominant negative mutant (Estus et al., 1994;Ham et al., 1995). Consistent with these observations, removal of survival factors leads to the activation of c-Jun N-terminal kinase (JNK), either alone or together with p38 mitogen-activated kinase, in a number of neuronal death paradigms, including PC12 cells (Xia et al., 1995), superior cervical ganglion (SCG) neurons (Ham et al., 1995;Eilers et al., 1998), and embryonic motoneurons (Maroney et al., 1998). In addition, phosphorylation of c-Jun and activation of JNK have been observed after neuronal injury in the adult rat brain (Herdegen et al., 1998) (for review, see Mielke and Herdegen, 2000). Taken together, these studies demonstrate that the pathways regulating both the level of c-Jun and its phosphorylation are crucial for the induction of neuronal cell death. Therefore, we were interested in identifying the upstream signaling pathways regulating the activation of the JNK-c-Jun pathway in neurons.Recently, we have shown that, in rat SCG neurons, the Rholike GTPases, Cdc42 and Rac1, are required for NGF withdrawal-induced death and that they induce apoptosis via activation of ...

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Dual Leucine Zipper-bearing Kinase (DLK) Activates p46SAPK and p38 but Not ERK2

Cited by 133 publications

References 47 publications

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

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

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

Evidence for a Role of Mixed Lineage Kinases in Neuronal Apoptosis

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