Mixed Lineage Kinase 3 Modulates β-Catenin Signaling in Cancer Cells

Thylur, Ramesh P.; Senthivinayagam, Subramanian; Campbell, E. M.; Velusamy, R.; Thorenoor, Nithyananda; Sondarva, Gautam; Mehrotra, Swati; Mishra, Prajna; Zook, Erin C.; Le, Phong T.; Rana, Ajay; Rana, Basabi

doi:10.1074/jbc.m111.298943

Cited by 26 publications

(13 citation statements)

References 49 publications

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“…Taken together, the down-regulation of DVL2, LEF1, CCND1 and c-MYC, and the up-regulation of DKK and FZD receptors suggest a role of mutant MLK3 as a molecular switch between canonic and non-canonic WNT signaling. In accordance, it was recently reported that MLK3 reduces the expression of β-catenin/TCF downstream targets by promoting the interaction between β-catenin and KLF4, a known repressor of β-catenin/TCF transcriptional activity [30]. Furthermore, in accordance with a role of PCP in colorectal cancer, FZD10 was recently demonstrated to be up-regulated in colorectal cancers and matched liver metastases, and its over-expression was associated with the activation of non-canonical WNT pathway [31,32].…”

Section: Resultssupporting

confidence: 66%

Dissecting the signaling pathways associated with the oncogenic activity of MLK3 P252H mutation

et al. 2014

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BackgroundMLK3 gene mutations were described to occur in about 20% of microsatellite unstable gastrointestinal cancers and to harbor oncogenic activity. In particular, mutation P252H, located in the kinase domain, was found to have a strong transforming potential, and to promote the growth of highly invasive tumors when subcutaneously injected in nude mice. Nevertheless, the molecular mechanism underlying the oncogenic activity of P252H mutant remained elusive.MethodsIn this work, we performed Illumina Whole Genome arrays on three biological replicas of human HEK293 cells stably transfected with the wild-type MLK3, the P252H mutation and with the empty vector (Mock) in order to identify the putative signaling pathways associated with P252H mutation.ResultsOur microarray results showed that mutant MLK3 deregulates several important colorectal cancer- associated signaling pathways such as WNT, MAPK, NOTCH, TGF-beta and p53, helping to narrow down the number of potential MLK3 targets responsible for its oncogenic effects. A more detailed analysis of the alterations affecting the WNT signaling pathway revealed a down-regulation of molecules involved in the canonical pathway, such as DVL2, LEF1, CCND1 and c-Myc, and an up-regulation of DKK, a well-known negative regulator of canonical WNT signaling, in MLK3 mutant cells. Additionally, FZD6 and FZD10 genes, known to act as negative regulators of the canonical WNT signaling cascade and as positive regulators of the planar cell polarity (PCP) pathway, a non-canonic WNT pathway, were found to be up-regulated in P252H cells.ConclusionThe results provide an overall view of the expression profile associated with mutant MLK3, and they support the functional role of mutant MLK3 by showing a deregulation of several signaling pathways known to play important roles in the development and progression of colorectal cancer. The results also suggest that mutant MLK3 may be a novel modulator of WNT signaling, and pinpoint the activation of PCP pathway as a possible mechanism underlying the invasive potential of MLK3 mutant cells.

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Section: Resultssupporting

confidence: 66%

Dissecting the signaling pathways associated with the oncogenic activity of MLK3 P252H mutation

et al. 2014

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“…However, very little is known about the expression and the mechanisms of MLK3 in MMs. MLK3 is promotes cell proliferation by strongly activating the extracellular regulated kinase (ERK) and β‐catenin pathways . Tumour necrosis factor (TNF) and epidermal growth factor (EGF) can stimulate MLK3 to activate multiple MAPK signalling further .…”

Section: Introductionmentioning

confidence: 99%

MLK3 promotes melanoma proliferation and invasion and is a target of microRNA-125b

et al. 2014

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“…VHL physically interacts with Krüppel-like factor 4 (KLF4), a transcription factor with roles in tumorigenesis [ 8 ]. Human KLF4 induces increased mouse PAX-2 and CTNNB1 mRNA expression [ 31 ] and, importantly, KLF4 binds to CTNNB1 inhibiting WNT signaling [ 13 , 34 ]. In addition, it has been shown that gain-of-function CTNNB1 mutant protein promotes increased expression of PAX-8 mRNA in mice [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Expression of renal cell markers and detection of 3p loss links endolymphatic sac tumor to renal cell carcinoma and warrants careful evaluation to avoid diagnostic pitfalls

Jester

Znoyko

Garnovskaya

et al. 2018

acta neuropathol commun

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Endolymphatic sac tumor (ELST) is a rare neoplasm arising in the temporal petrous region thought to originate from endolymphatic sac epithelium. It may arise sporadically or in association with Von-Hippel-Lindau syndrome (VHL). The ELST prevalence in VHL ranges from 3 to 16% and may be the initial presentation of the disease. Onset is usually in the 3rd to 5th decade with hearing loss and an indolent course. ELSTs present as locally destructive lesions with characteristic computed tomography imaging features. Histologically, they show papillary, cystic or glandular architectures. Immunohistochemically, they express keratin, EMA, and variably S100 and GFAP. Currently it is recommended that, given its rarity, ELST needs to be differentiated from other entities with similar morphologic patterns, particularly other VHL-associated neoplasms such as metastatic clear cell renal cell carcinoma (ccRCC). Nineteen ELST cases were studied. Immunohistochemistry (18/19) and single nucleotide polymorphism microarray testing was performed (12/19). Comparison with the immunophenotype and copy number profile in RCC is discussed. Patients presented with characteristic bone destructive lesions in the petrous temporal bones. Pathology of tumors showed characteristic ELST morphology with immunoexpression of CK7, GFAP, S100, PAX-8, PAX-2, CA-9 in the tumor cells. Immunostaines for RCC, CD10, CK20, chromogranin A, synaptophysin, TTF-1, thyroglobulin, and transthyretin were negative in the tumor cells. Molecular testing showed loss of 3p and 9q in 66% (8/12) and 58% (7/12) cases, respectively. Immunoreactivity for renal markers in ELST is an important diagnostic caveat and has not been previously reported. In fact, renal markers are currently recommended in order to rule out metastatic RCC although PAX gene complex and CA-9 have been implicated in the development of the inner ear. Importantly copy number assessment of ELST has not been previously reported. Loss of 3p (including the VHL locus) in ELST suggests similar mechanistic origins as ccRCC.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0607-0) contains supplementary material, which is available to authorized users.

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Mixed Lineage Kinase 3 Modulates β-Catenin Signaling in Cancer Cells

Cited by 26 publications

References 49 publications

Dissecting the signaling pathways associated with the oncogenic activity of MLK3 P252H mutation

Dissecting the signaling pathways associated with the oncogenic activity of MLK3 P252H mutation

MLK3 promotes melanoma proliferation and invasion and is a target of microRNA-125b

Expression of renal cell markers and detection of 3p loss links endolymphatic sac tumor to renal cell carcinoma and warrants careful evaluation to avoid diagnostic pitfalls

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