Hepsin regulates TGFβ signaling via fibronectin proteolysis

Belitškin, Denis; Pant, Shishir M.; Munne, Pauliina; Suleymanova, Ilida; Belitškina, Kati; Hongisto, Hanna-Ala; Englund, Johanna; Raatikainen, Tiina; Klezovitch, Olga; Vasioukhin, Valeri; Li, Shuo; Wu, Qingyu; Monni, Outi; Kuure, Satu; Laakkonen, Pirjo; Pouwels, Jeroen; Tervonen, Topi A.; Klefström, Juha

doi:10.15252/embr.202152532

Cited by 13 publications

(25 citation statements)

References 84 publications

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“…After activation of TGF-β signaling, TGF-β-associated ligands bind to corresponding receptors I and II ( de la Cruz-Merino et al, 2009 ) and then transfer extracellular signals to nuclear components through canonical TGF-β pathways, such as the TGF-β/Smad pathway, and noncanonical TGF-β pathways, such as the p38/mitogen-activated protein kinase (MAPK) pathway, GTP pathway, PI3K/AKT pathway, and NF-κB pathway ( Patil et al, 2011 ; Bataller et al, 2019 ; Chang and Pauklin, 2021 ; Choi et al, 2021 ; Hou et al, 2021 ). TGF-β has often been implicated in carcinogenesis, and studies have demonstrated that TGF-β has both oncogenic and tumor-suppressive functions in cancer regulation mechanisms ( Yu and Feng, 2019 ; Belitškin et al, 2021 ). The antitumor ability of TGF-β functions occur through cytostatic and proapoptotic effects ( Ahmadi et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

TGF-β Signaling Pathway-Based Model to Predict the Subtype and Prognosis of Head and Neck Squamous Cell Carcinoma

Guan

Xue

2022

Front. Genet.

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Background: Although immunotherapy with immune checkpoint therapy has been used to treat head and neck squamous cell carcinoma (HNSCC), response rates and treatment sensitivity remain limited. Recent studies have indicated that transforming growth factor-β (TGF-β) may be an important target for novel cancer immunotherapies.Materials and methods: We collected genomic profile data from The Cancer Genome Atlas and Gene Expression Omnibus. The least absolute shrinkage and selection operator method and Cox regression were used to establish a prognostic model. Gene set enrichment analysis was applied to explore biological functions. Tracking of indels by decomposition and subclass mapping algorithms were adopted to evaluate immunotherapy efficiency.Result: We established a seven TGF-β pathway-associated gene signature with good prediction efficiency. The high-risk score subgroup mainly showed enrichment in tumor-associated signaling such as hypoxia and epithelial-mesenchymal transition (EMT) pathways; This subgroup was also associated with tumor progression. The low-risk score subgroup was more sensitive to immunotherapy and the high-risk score subgroup to cisplatin, erlotinib, paclitaxel, and crizotinib.Conclusion: The TGF-β pathway signature gene model provides a novel perspective for evaluating effectiveness pre-immunotherapy and may guide further studies of precision immuno-oncology.

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Section: Discussionmentioning

confidence: 99%

TGF-β Signaling Pathway-Based Model to Predict the Subtype and Prognosis of Head and Neck Squamous Cell Carcinoma

Guan

Xue

2022

Front. Genet.

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“…The MCF10A (ATCC Cat# CRL-10317, RRID:CVCL_0598) cell line was obtained from the American Type Culture Collection and cultured as described previously [3] in MCDB 170 (US Biological, Salem, MA, USA) supplemented with 5 lgÁmL À1 insulin, 70 lgÁmL À1 bovine pituitary extract, 0.5 lLÁmL À1 hydrocortisone, 5 ngÁmL À1 EGF, 5 lgÁmL À1 human transferrin, and 0.01 lM isopropretenol (all from Sigma Aldrich, St.Louis, MO, USA). The MCF10A-based cell lines harboring the pLenti6-TGF-b1V5 and inducible hepsin overexpression constructs were published previously [3,8].…”

Section: Cell Linesmentioning

confidence: 99%

“…MCF10A growth experiments were performed in Cultrex RGF Basement Membrane Extract, Type 2 (R&D Systems, 3533-005-02, Minneapolis, MN, USA) 3D matrix and serum-free media as described in [3,8]. Human tumor samples were obtained from elective breast cancer surgeries between May 2019 and May 2020 at the Helsinki University Central Hospital (Ethical permit: 243/13/03/02/2013/TMK02 157 and HUS/ 2697/2019 approved by the Helsinki University Hospital Ethical Committee).…”

Section: D Cell and Pdec Culture Experimentsmentioning

confidence: 99%

“…Functions of this protease include regulation of epithelial integrity [3][4][5] and proteolytic activation of hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) [6,7]. We recently demonstrated that hepsin regulates transforming growth factor b (TGFb) signaling in the murine mammary gland and breast cancer models through a release of latent TGFb from extracellular matrix (ECM) storage [8]. In models of breast cancer, hepsin is required for oncogenic Ras-mediated loss of epithelial integrity and tumor progression [4].…”

Section: Introductionmentioning

confidence: 99%

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Hepsin promotes breast tumor growth signaling via the TGFβ‐EGFR axis

Belitškin,

Munne,

Pant

et al. 2023

Molecular Oncology

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Hepsin, a type II transmembrane serine protease, is commonly overexpressed in prostate and breast cancer. The hepsin protein is stabilized by the Ras‐MAPK pathway, and, downstream, this protease regulates the degradation of extracellular matrix components and activates growth factor pathways, such as the hepatocyte growth factor (HGF) and transforming growth factor beta (TGFβ) pathway. However, how exactly active hepsin promotes cell proliferation machinery to sustain tumor growth is not fully understood. Here, we show that genetic deletion of the gene encoding hepsin (Hpn) in a WAP‐Myc model of aggressive MYC‐driven breast cancer inhibits tumor growth in the primary syngrafted sites and the growth of disseminated tumors in the lungs. The suppression of tumor growth upon loss of hepsin was accompanied by downregulation of TGFβ and EGFR signaling together with a reduction in epidermal growth factor receptor (EGFR) protein levels. We further demonstrate in 3D cultures of patient‐derived breast cancer explants that both basal TGFβ signaling and EGFR protein expression are inhibited by neutralizing antibodies or small‐molecule inhibitors of hepsin. The study demonstrates a role for hepsin as a regulator of cell proliferation and tumor growth through TGFβ and EGFR pathways, warranting consideration of hepsin as a potential indirect upstream target for therapeutic inhibition of TGFβ and EGFR pathways in cancer.

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“…In the kidney, hepsin polymerizes uromodulin to inhibit bacterial infection in the urinary tract [17][18][19]. In breast cancers, hepsin cleaves fibronectin in the extracellular matrix to enhance transforming growth factor-beta signalling and cancer progression [20,21]. In the inner ear, hepsin is essential for auditory nerve function [22,23].…”

Section: Introductionmentioning

confidence: 99%

Spatial position is a key determinant of N‐glycan functionality of the scavenger receptor cysteine‐rich domain of human hepsin

Sun

Wang

et al. 2023

The FEBS Journal

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The scavenger receptor cysteine‐rich (SRCR) domain is a key constituent in diverse proteins. N‐glycosylation is important in protein expression and function. In the SRCR domain of different proteins, N‐glycosylation sites and functionality vary substantially. In this study, we examined the importance of N‐glycosylation site positions in the SRCR domain of hepsin, a type II transmembrane serine protease involved in many pathophysiological processes. We analysed hepsin mutants with alternative N‐glycosylation sites in the SRCR and protease domains using three‐dimensional modelling, site‐directed mutagenesis, HepG2 cell expression, immunostaining, and western blotting. We found that the N‐glycan function in the SRCR domain in promoting hepsin expression and activation on the cell surface cannot be replaced by alternatively created N‐glycans in the protease domain. Within the SRCR domain, the presence of an N‐glycan in a confined surface area was essential for calnexin‐assisted protein folding, endoplasmic reticulum (ER) exiting, and zymogen activation of hepsin on the cell surface. Hepsin mutants with alternative N‐glycosylation sites on the opposite side of the SRCR domain were trapped by ER chaperones, resulting in the activation of the unfolded protein response in HepG2 cells. These results indicate that the spatial N‐glycan positioning in the SRCR domain is a key determinant in the interaction with calnexin and subsequent cell surface expression of hepsin. These findings may help to understand the conservation and functionality of N‐glycosylation sites in the SRCR domains of different proteins.

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Hepsin regulates TGFβ signaling via fibronectin proteolysis

Cited by 13 publications

References 84 publications

TGF-β Signaling Pathway-Based Model to Predict the Subtype and Prognosis of Head and Neck Squamous Cell Carcinoma

TGF-β Signaling Pathway-Based Model to Predict the Subtype and Prognosis of Head and Neck Squamous Cell Carcinoma

Hepsin promotes breast tumor growth signaling via the TGFβ‐EGFR axis

Spatial position is a key determinant of N‐glycan functionality of the scavenger receptor cysteine‐rich domain of human hepsin

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