Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis

Marusiak, Anna A.; Stephenson, Natalie L.; Baik, Hayeon; Trotter, Eleanor W.; Li, Yaoyong; Blyth, Karen; Mason, Susan; Chapman, Phil; Puto, Lorena A.; Read, Jon; Brassington, C.; Pollard, Hannah; Phillips, Chris; Green, Isabelle; Overman, R.; Collier, Matthew; Testoni, Ewelina; Hunter, Tony; Sansom, Owen J.; Brognard, John

doi:10.1158/0008-5472.can-15-0701-t

Cited by 38 publications

(34 citation statements)

References 33 publications

(34 reference statements)

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“…These results are consistent with previous reports that MLK4 functions as a negative regulator of p38 and JNK signalling in HCT116 colon cancer cells, and negatively regulates Toll receptor signalling and LPS-induced ERK and JNK activation in murine macrophages [3, 4]. However, the results are contrary to findings that MLK4 is an activator of JNK in HCT15 colon cancer cells [14]. These studies employed different cell types that were cultured under different adherence conditions, and possibly the variation in these critical parameters influenced the effect of MLK4β expression on MAPK activation.…”

Section: Discussionsupporting

confidence: 91%

“…MLK3, the most extensively studied member of the MLK subfamily, has critical functions in migration and invasion in breast, gastric, and ovarian cancer cells; and MLK3 regulates neuronal cell apoptosis [9–12]. MLK3 has more than 70% sequence identity to the MLK4 catalytic domain; however, recent studies indicate non-redundant functions of these enzymes in normal and neoplastic cells [3, 4, 13, 14]. …”

Section: Introductionmentioning

confidence: 99%

“…MLK4 interacts with toll-like receptor 4 and suppresses lipopolysaccharide-induced c-Jun N-terminal kinase (JNK) and extracellular stimulus-regulated kinase (ERK) signalling [3]. Mutated MLK4 kinase has been detected in microsatellite stable colorectal tumours, and these mutant alleles have been characterized as being either loss-of-function or tumorigenic [14, 15]. Thus, MLK3 and MLK4 are important regulators of cellular transformation, and effective targeting of these enzymes in tumor cells requires a thorough understanding of MLK protein level and kinase activity modulation.…”

Section: Introductionmentioning

confidence: 99%

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Osmotic and heat stress-dependent regulation of MLK4β and MLK3 by the CHIP E3 ligase in ovarian cancer cells

Blessing

Kasturirangan

Zink

et al. 2017

Cellular Signalling

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Mixed Lineage Kinase 3 (MLK3), a member of the MLK subfamily of protein kinases, is a mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) that activates MAPK signalling pathways and regulates cellular responses such as proliferation, invasion and apoptosis. MLK4β, another member of the MLK subfamily, is less extensively studied, and the regulation of MLK4β by stress stimuli is not known. In this study, the regulation of MLK4β and MLK3 by osmotic stress, thermostress and heat shock protein 90 (Hsp90) inhibition was investigated in ovarian cancer cells. MLK3 and MLK4β protein levels declined under conditions of prolonged osmotic stress, heat stress or exposure to the Hsp90 inhibitor geldanamycin (GA); and MLK3 protein declined faster than MLK4β.–Similar to MLK3, the reduction in MLK4β protein in cells exposed to heat or osmotic stresses occurred via a mechanism that involves the E3 ligase, carboxy-terminus of Hsc70-interacting protein (CHIP). Both heat shock protein 70 (Hsp70) and CHIP overexpression led to polyubiquitination and a decrease in endogenous MLK4β protein, and MLK4β was ubiquitinated by CHIP in vitro. In untreated cells and cells exposed to osmotic and heat stresses for short time periods, small interfering RNA (siRNA) knockdown of MLK4β elevated the levels of activated MLK3, c-Jun N-terminal kinase (JNK) and p38 MAPKs. Furthermore, MLK3 binds to MLK4β, and this association is regulated by osmotic stress. These results suggest that in the early response to stressful stimuli, MLK4β-MLK3 binding is important for regulating MLK3 activity and MAPK signalling, and after prolonged periods of stress exposure, MLK4β and MLK3 proteins decline via CHIP-dependent degradation. These findings provide insight into how heat and osmotic stresses regulate MLK4β and MLK3, and reveal an important function for MLK4β in modulating MLK3 activity in stress responses.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Osmotic and heat stress-dependent regulation of MLK4β and MLK3 by the CHIP E3 ligase in ovarian cancer cells

Blessing

Kasturirangan

Zink

et al. 2017

Cellular Signalling

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“…Aberrant expression and activation of JNK are often observed in many cancer cell lines and in patient tissues [27]. The role of JNK is controversial, as it has been shown to be a positive regulator of CRC metastasis as shown in this study and other reports [14, 42], whereas other studies demonstrated a role of JNK as a tumor suppressor in CRC [43]. Studies in mice have demonstrated that the contribution of JNK is cell type and isoform specific, which may explain the seemingly opposite role of JNK in promoting cell survival and proliferation on one hand and cell death on the other [25].…”

Section: Discussionmentioning

confidence: 58%

Extracellular translationally controlled tumor protein promotes colorectal cancer invasion and metastasis through Cdc42/JNK/ MMP9 signaling

et al. 2016

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The translationally controlled tumor protein (TCTP) can be secreted independently of the endoplasmic reticulum/Golgi pathway and has extrinsic activities when it is characterized as the histamine releasing factor (HRF). Despite its important role in allergies and inflammation, little is known about how extracellular TCTP affects cancer progression. In this study, we found that TCTP was overexpressed in the interstitial tissue of colorectal cancer (CRC) and its expression correlated with poor survival, high pathological grades and metastatic TNM stage in CRC patients. TCTP expression was greater in metastatic liver tissue than in primary tumors and was increased in highly invasive CRC cells. We demonstrated that the expression of TCTP was regulated by HIF-1α and its release was increased in response to low serum and hypoxic stress. Recombinant human TCTP (rhTCTP) promoted the migration and invasiveness of CRC cells in vitro and contributed to distant liver metastasis in vivo. Furthermore, rhTCTP activated Cdc42, phosphorylated JNK (p-JNK), increasing the translocation of p-JNK from the cytoplasm to the nucleus, as well as the secretion of MMP9. In addition, the expression of TCTP positively correlated with that of Cdc42 and p-JNK in clinical CRC samples. The silencing of Cdc42, JNK and MMP9 significantly inhibited the Matrigel invasion of rhTCTP-enhanced CRC cells. Collectively, these results identify a new role for extracellular TCTP as a promoter of CRC progression and liver metastases via Cdc42/JNK/MMP9 activation.

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“…In the pan-cancer analyses we found only a single novel SMG, which was not either present in the curated COSMIC Cancer Gene Census or found by Martincorena et al 26 . This gene, MLK4 (q=2e -4 ), is a mixed lineage kinase that regulates the JNK,P38 and ERK signaling pathways and has been reported to inhibit tumorigenesis in colorectal cancer 27 . In addition, in our tumor type-specific analyses, which for several tumor types is limited by the number of samples, we identified a novel metastatic breast cancer-specific SMG -ZFPM1 (also known as Friend of GATA1 (FOG1), q=8e -5 ), a zinc-finger transcription factor protein without clear links with cancer.…”

Section: Significantly Mutated Genesmentioning

confidence: 99%

Pan-cancer whole genome analyses of metastatic solid tumors

Priestley

Baber

Lolkema

et al. 2018

Preprint

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Metastatic cancer is one of the major causes of death and is associated with poor treatment efficiency. A better understanding of the characteristics of late stage cancer is required to help tailor personalised treatment, reduce overtreatment and improve outcomes. Here we describe the largest pan-cancer study of metastatic solid tumor genomes, including 2,520 whole genome-sequenced tumor-normal pairs, analyzed at a median depth of 106x and 38x respectively, and surveying over 70 million somatic variants. Metastatic lesions were found to be very diverse, with mutation characteristics reflecting those of the primary tumor types, although with high rates of whole genome duplication events (56%). Metastatic lesions are relatively homogeneous with the vast majority (96%) of driver mutations being clonal and up to 80% of tumor suppressor genes bi-allelically inactivated through different mutational mechanisms. For 62% of all patients, genetic variants that may be associated with outcome of approved or experimental therapies were detected. These actionable events were distributed across various mutation types underlining the importance of comprehensive genomic tumor profiling for cancer precision medicine. Code availabilityAll bioinformatic analysis tools and scripts used are available at https://github.com/hartwigmedical/.

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Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis

Cited by 38 publications

References 33 publications

Osmotic and heat stress-dependent regulation of MLK4β and MLK3 by the CHIP E3 ligase in ovarian cancer cells

Osmotic and heat stress-dependent regulation of MLK4β and MLK3 by the CHIP E3 ligase in ovarian cancer cells

Extracellular translationally controlled tumor protein promotes colorectal cancer invasion and metastasis through Cdc42/JNK/ MMP9 signaling

Pan-cancer whole genome analyses of metastatic solid tumors

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