Extracellular citrullination inhibits the function of matrix associated TGF-β

Sipilä, Kalle; Ranga, Vipin; Rappu, Pekka; Torittu, Annamari; Pirilä, Laura; Käpylä, Jarmo; Johnson, Mark S.; Larjava, Hannu; Heino, Jyrki

doi:10.1016/j.matbio.2016.02.008

Cited by 16 publications

(12 citation statements)

References 52 publications

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“…TGF-β signaling has been recognized as critical to CRC liver metastasis 38 and we found upregulation of the TGF-β binding proteins LTBP1-3, TSP1, and TSP2, some of which contribute to TGF-β activation 39 , 40 . TGF-β has been linked to tumor suppression through EMT 42 , and citrullination of TGF-β altered its activity 42 . The complex balance between these signals and the function of epithelial-mesenchymal plasticity in cancer is still not completely understood.…”

Section: Discussionmentioning

confidence: 99%

Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix

et al. 2018

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Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix component collagen type I promotes greater adhesion and decreased migration of CRC cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition and liver metastasis. Overall, our study reveals the potential for PAD4-dependant citrullination to drive the progression of CRC liver metastasis.

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Section: Discussionmentioning

confidence: 99%

Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix

et al. 2018

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“…68 Both proteins were identified as citrullinated in the context of RA. 69 Modified peptides spectra clearly evidence the citrulline effect characterized by an enhanced cleavage preference at the C-terminus of citrullinated residues upon collision-induced dissociation (CID) tandem mass spectrometry, which results in a marked abundance of series y ions for tryptic peptides. 70 Fert-Bober and team assumed a different approach to identify, quantify, and validate citrullination residues while circumventing the challenges associated with current methods in preparing samples and analyzing data.…”

Section: Overcoming Misidentification Of Citrullinationmentioning

confidence: 99%

Elucidating Citrullination by Mass Spectrometry and Its Role in Disease Pathogenesis

et al. 2020

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This review focuses on discussing key mechanisms in disease pathogenesis mediated by the protein post-translational modification citrullination. These processes are discussed in depth in the context of complex diseases such as rheumatoid arthritis, cancer, central nervous system disorders, and cardiovascular disease. Additionally, a critical evaluation of challenges in laboratory detection of citrullination sites is also outlined. In this context, the role of mass spectrometry is discussed with a focus on contemporary techniques that offer promising options to detect the exact site of protein citrullination. Novel methods described in the paper have the potential to detect and quantify the occurrence of post-translational modification sites for diagnosis and therapeutic purposes with a high degree of specificity and sensitivity. Furthermore, they offer a much faster performance than traditional techniques making them ideal for large-scale experimentation.

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“…During tumorigenesis, a crosstalk between tumor and stromal cells modifies the microenvironment and the ECM . The expression of biglycan by stromal fibroblasts is induced by TGF‐β, a multipurpose growth factor which might then use the TLR2/4 on stromal macrophages to further modulate the tumor microenvironment and to induce the recruitment of tumor cells through chemokine production. In addition, biglycan is able to increase the affinity of TGF‐β to its receptor and therefore promote cancer progression.…”

Section: Inflammatory Biglycan Signaling In Tumor Cell Biologymentioning

confidence: 99%

Proteoglycan neofunctions: regulation of inflammation and autophagy in cancer biology

et al. 2016

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Inflammation and autophagy have emerged as prominent issues in the context of proteoglycan signaling. In particular, two small, leucine-rich proteoglycans, biglycan and decorin, play pivotal roles in the regulation of these vital cellular pathways and, as such, are intrinsically involved in cancer initiation and progression. In this minireview we will address novel functions of biglycan and decorin in inflammation and autophagy, and analyze new emerging signaling events triggered by these proteoglycans, which directly or indirectly modulate these processes. We will critically discuss the dual role of proteoglycan-driven inflammation and autophagy in tumor biology, and delineate the potential mechanisms through which soluble ECM constituents affect the microenvironment associated with inflammatory and neoplastic diseases.

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Extracellular citrullination inhibits the function of matrix associated TGF-β

Cited by 16 publications

References 52 publications

Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix

Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix

Elucidating Citrullination by Mass Spectrometry and Its Role in Disease Pathogenesis

Proteoglycan neofunctions: regulation of inflammation and autophagy in cancer biology

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