Induced, selective proteolysis of MLK3 negatively regulates MLK3/JNK signalling

Liou, Geou-Yarh; Zhang, Hua; Miller, Eva M.; Seibold, Steve A.; Chen, Weiqin; Gallo, Kathleen A.

doi:10.1042/bj20091077

Cited by 5 publications

(4 citation statements)

References 54 publications

(59 reference statements)

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“…This cleavage produces a C-terminal fragment that heterodimerizes with full-length MLK3 and reduces MLK3 activation loop phosphorylation and MLK3-dependent activation of JNK. Furthermore, production of the C-terminal fragment is blocked by proteasome inhibition (52). A previous study by Gonda et al showed that the Drosophila melanogaster MLK Slipper (Slpr) is phosphorylated in response to heat stress on a serine that is within a MAPK PXSP consensus sequence (53).…”

Section: Discussionmentioning

confidence: 99%

“…(C) Reactions and immunoblotting were carried out as described above for panel A with the following E2 enzymes: UbcH5a, -b, -c, and -d; Ubc13/Uev1a plus Ube2W (13/2W); Ubc13/Uev1a plus Cdc34 (13/Cdc34); UbcH8; and UbcH9. enous MLK3 undergoes proteolytic cleavage at a site within the kinase domain in response to phorbol-12-myristate-13-acetate (PMA) and TNF (52). This cleavage produces a C-terminal fragment that heterodimerizes with full-length MLK3 and reduces MLK3 activation loop phosphorylation and MLK3-dependent activation of JNK.…”

Section: Discussionmentioning

confidence: 99%

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The E3 Ligase CHIP Mediates Ubiquitination and Degradation of Mixed-Lineage Kinase 3

Blessing

Brockman

Chadee

2014

Molecular and Cellular Biology

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Mixed-lineage kinase 3 (MLK3) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that has regulatory roles in diverse biological processes such as proliferation, migration, differentiation, invasion, and neuronal cell apoptosis (1-9). MLK3 activates the c-Jun N-terminal kinase (JNK) and p38 MAPK signaling pathways, and in certain cellular contexts, MLK3 has a kinase-independent function in the activation of extracellular signal-regulated kinase (ERK) MAPK signaling (1, 10-12). Aberrant levels of total and/or activated MLK3 protein have been observed in ovarian and breast cancer cells in comparison to nonneoplastic ovarian and breast epithelial cells (5, 6). Moreover, a critical function for MLK3 in breast and ovarian cancer cell invasion was recently identified (5, 6). The regulation of MLK3 by phosphorylation, dimerization, and interaction with Rho GTPases has been the focus of numerous studies; however, the mechanism(s) that controls the level of total MLK3 protein in cells remains poorly understood (13-16).We previously identified that in SKOV3 ovarian cancer cells, the proinflammatory cytokines tumor necrosis factor alpha (TNF-␣) and interleukin-1␤ (IL-1␤) induced the activation of MLK3 and that TNF-␣ also stimulated MLK3 ubiquitination (17). TNF-␣-dependent activation of MLK3 is facilitated by TNF receptor-associated factor 2 (TRAF2) and TRAF6, which interact with MLK3 and are recruited to the TNF receptor (17,18). Recently, it was demonstrated that TRAF6 promotes K63-linked polyubiquitination of MLK3 in vitro (19). Furthermore, MLK3 activation in response to IL-1␤ is dependent on TRAF6 binding and K63-linked polyubiquitination (17,19). MLK3 also undergoes K48-linked polyubiquitination; however, the role of this modification in MLK3 protein function and turnover has not been elucidated (17).MLK3 interacts with the chaperone protein Hsp90 and the cochaperone protein p50cdc37, which participate in the folding and stabilization of signaling proteins involved in proliferation, apoptosis, and survival (20, 21). The dissociation of Hsp90 from its client proteins can be triggered by specific stimuli or by exposure to Hsp90 ATPase inhibitors such as geldanamycin (GA) (22,23). Treatment of cancer cell lines with GA causes a reduction in the level of endogenous MLK3 protein and an inhibition of JNK signaling, which suggests that the Hsp90-MLK3 interaction is important for MLK3 function and stability (21,24). The disruption of Hsp90 chaperone-client interactions can lead to ubiquitination and proteasomal degradation of the client proteins via Hsp70-dependent recruitment of the carboxyl terminus of Hsc70-interacting protein (CHIP) E3 ubiquitin ligase (20,22,23). CHIP is a Ubox E3 protein that mediates cytosolic protein polyubiquitination and targets Hsp70-bound proteins for degradation by the 26S proteasome, thereby coupling the chaperone and ubiquitin-proteasome systems (25)(26)(27)(28). In this study, we investigated the role of CHIP in the ubiquitination and degradation of MLK3 in response to GA, hea...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The E3 Ligase CHIP Mediates Ubiquitination and Degradation of Mixed-Lineage Kinase 3

Blessing

Brockman

Chadee

2014

Molecular and Cellular Biology

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“…MLK3, also known as MAP3K11, Src-homology 3 (SH3) domain-containing proline-rich kinase (SPRK), protein-tyrosine kinase 1 (PTK1), and slipper ( Drosophila ), was first identified in 1994 [ 11 , 14 , 15 ]. This 847-amino acid protein is the only member in the MLK subfamily that has been extensively studied in terms of regulation, functions and implications in human diseases [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. MLK3, as its name MAP3K11 implies, functions as a MAP3K to phosphorylate and activate specific MAP2Ks, which in turn activate specific MAPKs.…”

Section: Mlk3mentioning

confidence: 99%

MLK3 Signaling in Cancer Invasion

Rattanasinchai

Gallo

2016

Cancers

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Mixed-lineage kinase 3 (MLK3) was first cloned in 1994; however, only in the past decade has MLK3 become recognized as a player in oncogenic signaling. MLK3 is a mitogen-activated protein kinase kinase kinase (MAP3K) that mediates signals from several cell surface receptors including receptor tyrosine kinases (RTKs), chemokine receptors, and cytokine receptors. Once activated, MLK3 transduces signals to multiple downstream pathways, primarily to c-Jun terminal kinase (JNK) MAPK, as well as to extracellular-signal-regulated kinase (ERK) MAPK, P38 MAPK, and NF-κB, resulting in both transcriptional and post-translational regulation of multiple effector proteins. In several types of cancer, MLK3 signaling is implicated in promoting cell proliferation, as well as driving cell migration, invasion and metastasis.

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“…These mechanisms include relief of inhibition, dimerization, posttranslational modification, scaffolding, proteolysis, and changes in subcellular localization [40], [41], [42], [43], [44]. In one instance, mammalian MLK3 is phosphorylated by JNK as a means of positive feedback [42].…”

Section: Introductionmentioning

confidence: 99%

Drosophila Heat Shock Response Requires the JNK Pathway and Phosphorylation of Mixed Lineage Kinase at a Conserved Serine-Proline Motif

Gonda

Garlena²,

Stronach³

2012

PLoS ONE

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Defining context specific requirements for proteins and pathways is a major challenge in the study of signal transduction. For example, the stress-activated protein kinase (SAPK) pathways are comprised of families of closely related transducers that are activated in a variety of tissues and contexts during development and organismal homeostasis. Consequently, redundant and pleiotropic effects have hampered a complete understanding of the individual contributions of transducers in distinct contexts. Here, we report on the function of a context-specific regulatory phosphorylation site, PXSP, in the Drosophila mixed lineage kinase protein, Slpr, a mitogen-activated protein kinase kinase kinase (MAP3K) in the Jun Kinase (JNK) pathway. Genetic analysis of the function of non-phosphorylatable (PXAP) and phosphomimetic mutant (PXEP) Slpr transgenes in several distinct contexts revealed minimal effects in JNK-dependent tissue closure processes but differential requirements in heat stress response. In particular, PXAP expression resulted in sensitivity of adults to sustained heat shock, like p38 and JNK pathway mutants. In contrast, PXEP overexpression conferred some resistance. Indeed, phosphorylation of the PXSP motif is enriched under heat shock conditions and requires in part, the p38 kinases for the enrichment. These data suggest that coordination of signaling between p38 and Slpr serves to maintain JNK signaling during heat stress. In sum, we demonstrate a novel role for JNK signaling in the heat shock response in flies and identify a posttranslational modification on Slpr, at a conserved site among MAP3K mixed lineage kinase family members, which bolsters stress resistance with negligible effects on JNK-dependent developmental processes.

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Induced, selective proteolysis of MLK3 negatively regulates MLK3/JNK signalling

Cited by 5 publications

References 54 publications

The E3 Ligase CHIP Mediates Ubiquitination and Degradation of Mixed-Lineage Kinase 3

The E3 Ligase CHIP Mediates Ubiquitination and Degradation of Mixed-Lineage Kinase 3

MLK3 Signaling in Cancer Invasion

Drosophila Heat Shock Response Requires the JNK Pathway and Phosphorylation of Mixed Lineage Kinase at a Conserved Serine-Proline Motif

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