HUNK phosphorylates EGFR to regulate breast cancer metastasis

Phelps-Polirer, Kendall; Dingle, Ivan P.; Williams, Christina J.; Rhett, J. Matthew; Eblen, Scott T.; Armeson, Kent; Hill, Elizabeth G.; Yeh, Elizabeth S.

doi:10.1038/s41388-019-1046-5

Cited by 31 publications

(52 citation statements)

References 40 publications

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“…EGFR has been used as an effective therapeutic target for tyrosine kinase inhibitors in lung and pancreatic cancers 32,33 . Furthermore, the activation of EGFR to promote tumor metastasis has been widely proven in various tumors [34][35][36] .…”

Section: Discussionmentioning

confidence: 99%

WFDC2 suppresses prostate cancer metastasis by modulating EGFR signaling inactivation

et al. 2020

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WAP four-disulfide core domain 2 (WFDC2) is a small secretory protein that has been widely studied in ovarian cancer. It has been proven that WFDC2 promotes proliferation and metastasis in ovarian cancer, and serves as a diagnostic biomarker. However, the specific function of WFDC2 in prostate cancer has not been reported. Here, we first screened the diagnostic marker and favorable prognostic factor WFDC2 in prostate cancer by bioinformatics. WFDC2 expression was negatively correlated with Gleason score and metastasis in prostate cancer. Then, we revealed that overexpression of WFDC2, and addition of recombinant protein HE4 can significantly inhibit prostate cancer metastasis in vivo and in vitro. By co-immunoprecipitation and co-localization assays, we proved that WFDC2 binds to the extracellular domain of epidermal growth factor receptor (EGFR). Immunoblot showed that WFDC2 overexpression and recombinant protein HE4 addition inactivated the EGFR/AKT/GSK3B/Snail signaling pathway, and then restrained the progression of epithelial-mesenchymal transition. In conclusion, our study identified that the tumor suppressor WFDC2 can suppress prostate cancer metastasis by inactivating EGFR signaling.

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Section: Discussionmentioning

confidence: 99%

WFDC2 suppresses prostate cancer metastasis by modulating EGFR signaling inactivation

et al. 2020

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“…The growth factor FGF18 regulates development of the neural system, specifically the midbrain structure [46]. Finally, HUNK is a serine/threonine kinase, which was recently shown to be associated with control of expression of E-cadherin [47], a molecule that can act as a receptor for pathogens [48]. We identified a 1-bp deletion in the 3′UTR region of the HUNK gene, which was fixed in the line with a low V E of LS and absent in the line with a high V E of LS.…”

Section: Discussionmentioning

confidence: 99%

Identification of functional mutations associated with environmental variance of litter size in rabbits

et al. 2020

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Background: Environmental variance (V E) is partly under genetic control and has recently been proposed as a measure of resilience. Unravelling the genetic background of the V E of complex traits could help to improve resilience of livestock and stabilize their production across farming systems. The objective of this study was to identify genes and functional mutations associated with variation in V E of litter size (LS) in rabbits. To achieve this, we combined the results of a genome-wide association study (GWAS) and a whole-genome sequencing (WGS) analysis using data from two divergently selected rabbit lines for high and low V E of LS. These lines differ in terms of biomarkers of immune response and mortality. Moreover, rabbits with a lower V E of LS were found to be more resilient to infections than animals with a higher V E of LS. Results: By using two GWAS approaches (single-marker regression and Bayesian multiple-marker regression), we identified four genomic regions associated with V E of LS, on chromosomes 3, 7, 10, and 14. We detected 38 genes in the associated genomic regions and, using WGS, we identified 129 variants in the splicing, UTR, and coding (missense and frameshift effects) regions of 16 of these 38 genes. These genes were related to the immune system, the development of sensory structures, and stress responses. All of these variants (except one) segregated in one of the rabbit lines and were absent (n = 91) or fixed in the other one (n = 37). The fixed variants were in the HDAC9, ITGB8, MIS18A, ENSOCUG00000021276 and URB1 genes. We also identified a 1-bp deletion in the 3′UTR region of the HUNK gene that was fixed in the low V E line and absent in the high V E line. Conclusions: This is the first study that combines GWAS and WGS analyses to study the genetic basis of V E. The new candidate genes and functional mutations identified in this study suggest that the V E of LS is under the control of functions related to the immune system, stress response, and the nervous system. These findings could also explain differences in resilience between rabbits with homogeneous and heterogeneous V E of litter size.

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“…However, our conclusions from the use of the MDA MB 468 cell line differed from this particular study. We showed that shRNA depletion of HUNK reduced cell migration and invasion compared to cells expressing a non-functional shRNA control, whereas the prior study showed that overexpression of HUNK suppresses migration and invasion [10,12]. While the use of individual reagents and techniques could certainly be attributed to the differences in results, another possibility is that exogenous HUNK could act as a dominant negative toward endogenous protein.…”

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confidence: 71%

“…al., our findings showed that HUNK is pro-metastatic. Separate from the two prior studies, our study showed that HUNK phosphorylates the epidermal growth factor receptor (EGFR) at threonine (T) 654 to regulate breast cancer metastasis, providing a discrete HUNK-kinase dependent mechanism for this process [10]. Our study used the 4T1 mouse mammary tumor cell line as well as two human basal breast cancer cell lines, the MDA MB 468 and BT20 model.…”

mentioning

confidence: 89%

“…Our study significantly differed from either of the prior studies because we identified a direct substrate of HUNK that provided a mechanism for the metastatic behavior of the mammary tumor and breast cancer cell lines we tested. To date, very few HUNK substrates are identified [7,10,18,19]. Three of the proteins identified as HUNK substrates; EGFR, Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (RUBICON), and integral membrane protein 2A (ITM2A), are described in the context of breast cancer [7,10,19].…”

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confidence: 99%

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HUNK Signaling in Metastatic Breast Cancer

2020

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Once metastatic disease has occurred, there is no cure for breast cancer. Consequently, identifying factors that promote and support breast cancer metastasis is critical for understanding how to pharmacologically target this process. Hormonally up-regulated neu-associated kinase (HUNK) is a serine/threonine protein kinase related to the sucrose non-fermenting-1 (Snf-1)/5' adenosine monophosphate-activated protein kinase (AMPK) family of kinases. HUNK has been found to play a role in breast cancer metastasis. However, conflicting reports indicate HUNK is a metastasis promoting factor as well as an inhibiting factor. Our group recently provided evidence that supports the conclusion that HUNK is a metastasis promoting factor by showing that HUNK regulates breast cancer metastasis through phosphorylation of EGFR. Here, we summarize our findings and discuss their implications toward pharmacological targeting of HUNK in breast cancer.

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HUNK phosphorylates EGFR to regulate breast cancer metastasis

Cited by 31 publications

References 40 publications

WFDC2 suppresses prostate cancer metastasis by modulating EGFR signaling inactivation

WFDC2 suppresses prostate cancer metastasis by modulating EGFR signaling inactivation

Identification of functional mutations associated with environmental variance of litter size in rabbits

HUNK Signaling in Metastatic Breast Cancer

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