BRK Targets Dok1 for Ubiquitin-Mediated Proteasomal Degradation to Promote Cell Proliferation and Migration

Miah, Sayem; Goel, Raghuveera Kumar; Dai, Chenlu; Kalra, Natasha; Beaton-Brown, Erika; Bagu, Edward T.; Bonham, Keith; Lukong, Kiven Erique

doi:10.1371/journal.pone.0087684

Cited by 17 publications

(16 citation statements)

References 88 publications

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“…Cancer cells with degradation of DOK1 by BRK acquire more aggressive phenotypes. 32. TM4SF4, a member of the tetraspanin L6 domain family, has been reported to be overexpressed in radiation-resistant lung cancer cells 33.…”

Section: Discussionmentioning

confidence: 99%

mRNA and methylation profiling of radioresistant esophageal cancer cells: the involvement of Sall2 in acquired aggressive phenotypes

Luo¹,

Wang²,

Tang³

et al. 2017

J. Cancer

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Esophageal squamous cell carcinoma (ESCC) is one of the deadliest malignancies worldwide. Radiotherapy plays a critical role in the curative management of inoperable ESCC patients. However, radioresistance restricts the efficacy of radiotherapy for ESCC patients. The molecules involved in radioresistance remain largely unknown, and new approaches to sensitize cells to irradiation are in demand. Technical advances in analysis of mRNA and methylation have enabled the exploration of the etiology of diseases and have the potential to broaden our understanding of the molecular pathways of ESCC radioresistance. In this study, we constructed radioresistant TE-1 and Eca-109 cell lines (TE-1/R and Eca-109/R, respectively). The radioresistant cells showed an increased migration ability but reduced apoptosis and cisplatin sensitivity compared with their parent cells. mRNA and methylation profiling by microarray revealed 1192 preferentially expressed mRNAs and 8841 aberrantly methylated regions between TE-1/R and TE-1 cells. By integrating the mRNA and methylation profiles, we related the decreased expression of transcription factor Sall2 with a corresponding increase in its methylation in TE-1/R cells, indicating its involvement in radioresistance. Upregulation of Sall2 decreased the growth and migration advantage of radioresistant ESCC cells. Taken together, our present findings illustrate the mRNA and DNA methylation changes during the radioresistance of ESCC and the important role of Sall2 in esophageal cancer malignancy.

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Section: Discussionmentioning

confidence: 99%

mRNA and methylation profiling of radioresistant esophageal cancer cells: the involvement of Sall2 in acquired aggressive phenotypes

Luo¹,

Wang²,

Tang³

et al. 2017

J. Cancer

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“…No previous studies have examined the effect of FRK activation on its tumor suppressor function. We have previously shown that the constitutively active variant of BRK significantly promoted the oncogenic properties of the enzyme [ 28 , 31 ]. Stable overexpression of FRK in the Basal B/FRK-negative MDA-MB-231 breast cancer cell line resulted in reduced cell proliferation, migration, invasion, and colony formation.…”

Section: Discussionmentioning

confidence: 99%

FRK inhibits breast cancer cell migration and invasion by suppressing epithelial-mesenchymal transition

et al. 2017

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The human fyn-related kinase (FRK) is a non-receptor tyrosine kinase known to have tumor suppressor activity in breast cancer cells. However, its mechanism of action has not been fully characterized. We generated FRK-stable MDA-MB-231 breast cancer cell lines and analyzed the effect on cell proliferation, migration, and invasiveness. We also used kinome analysis to identify potential FRK-regulated signaling pathways. We employed both immunoblotting and RT-PCR to identify/validate FRK-regulated targets (proteins and genes) in these cells. Finally, we interrogated the TCGA and GENT gene expression databases to determine the correlation between the expression of FRK and epithelial/mesenchymal markers. We observed that FRK overexpression suppressed cell proliferation, migration, and invasiveness, inhibited various JAK/STAT, MAPK and Akt signaling pathways, and suppressed the expression of some STAT3 target genes. Also, FRK overexpression increased the expression of epithelial markers including E-cadherin mRNA and down-regulated the transcript levels of vimentin, fibronectin, and slug. Finally, we observed an inverse correlation between FRK expression and mesenchymal markers in a large cohort of breast cancer cells. Our data, therefore, suggests that FRK represses cell proliferation, migration and invasiveness by suppressing epithelial to mesenchymal transition.

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“…Loss of FL p62 DOK1 as a tumor suppressor is a common event in human cancers, including solid tumors ( Berger et al, 2010 , Saulnier et al, 2012 ). Oncogenic kinases ( Janas and Van Aelst, 2011 , Miah et al, 2014 ) and viruses ( Siouda et al, 2014 ) facilitate proteasomal degradation of DOK1 and epigenetic silencing of the DOK1 gene. In contrast, agents that promote stress responses (such as E2F) ( Siouda et al, 2012 ) and differentiation, e.g.…”

Section: Introductionmentioning

confidence: 99%

Subcellular compartmentalization of docking protein-1 contributes to progression in colorectal cancer

et al. 2016

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Full-length (FL) docking protein-1 (DOK1) is an adapter protein which inhibits growth factor and immune response pathways in normal tissues, but is frequently lost in human cancers. Small DOK1 variants remain in cells of solid tumors and leukemias, albeit, their functions are elusive. To assess the so far unknown role of DOK1 in colorectal cancer (CRC), we generated DOK1 mutants which mimic the domain structure and subcellular distribution of DOK1 protein variants in leukemia patients. We found that cytoplasmic DOK1 activated peroxisome-proliferator-activated-receptor-gamma (PPARγ) resulting in inhibition of the c-FOS promoter and cell proliferation, whereas nuclear DOK1 was inactive. PPARγ-agonist increased expression of endogenous DOK1 and interaction with PPARγ. Forward translation of this cell-based signaling model predicted compartmentalization of DOK1 in patients. In a large series of CRC patients, loss of DOK1 protein was associated with poor prognosis at early tumor stages (*p = 0.001; n = 1492). In tumors with cytoplasmic expression of DOK1, survival was improved, whereas nuclear localization of DOK1 correlated with poor outcome, indicating that compartmentalization of DOK1 is critical for CRC progression. Thus, DOK1 was identified as a prognostic factor for non-metastatic CRC, and, via its drugability by PPARγ-agonist, may constitute a potential target for future cancer treatments.

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BRK Targets Dok1 for Ubiquitin-Mediated Proteasomal Degradation to Promote Cell Proliferation and Migration

Cited by 17 publications

References 88 publications

mRNA and methylation profiling of radioresistant esophageal cancer cells: the involvement of Sall2 in acquired aggressive phenotypes

mRNA and methylation profiling of radioresistant esophageal cancer cells: the involvement of Sall2 in acquired aggressive phenotypes

FRK inhibits breast cancer cell migration and invasion by suppressing epithelial-mesenchymal transition

Subcellular compartmentalization of docking protein-1 contributes to progression in colorectal cancer

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