Processing by Convertases Is Required for Glypican-3-induced Inhibition of Hedgehog Signaling

Capurro, Mariana; Shi, Wen; Izumikawa, Tomomi; Kitagawa, Hiroshi; Filmus, Jorge

doi:10.1074/jbc.m114.612705

Cited by 29 publications

(29 citation statements)

References 29 publications

(44 reference statements)

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“…Moreover, purified glypican-3 binds with high affinity to Indian and Sonic Hh as well as it competes with Patched for Hh binding [ 83 , 89 ]. A recent study has shown that processing by convertases is required for GPC3-evoked suppression of Hh signaling, and this process is dependent on the HS chains and their degree of sulfation [ 90 ]. Thus, the glypican family is not only complex in nature, but is also the control of various modifying enzymes (proteases and lipases) that modulate its biological activity.…”

Section: Cell Surface Proteoglycansmentioning

confidence: 99%

Proteoglycan form and function: A comprehensive nomenclature of proteoglycans

2015

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We provide a comprehensive classification of the proteoglycan gene families and respective protein cores. This updated nomenclature is based on three criteria: Cellular and subcellular location, overall gene/protein homology, and the utilization of specific protein modules within their respective protein cores. These three signatures were utilized to design four major classes of proteoglycans with distinct forms and functions: the intracellular, cell-surface, pericellular and extracellular proteoglycans. The proposed nomenclature encompasses forty-three distinct proteoglycan-encoding genes and many alternatively-spliced variants. The biological functions of these four proteoglycan families are critically assessed in development, cancer and angiogenesis, and in various acquired and genetic diseases where their expression is aberrant.

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Section: Cell Surface Proteoglycansmentioning

confidence: 99%

Proteoglycan form and function: A comprehensive nomenclature of proteoglycans

2015

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“…Of note, the core protein of GPC3 can directly bind Hh to inhibit its signaling activity in cell culture (26). In a later study, experimental evidence demonstrated that cleavage by convertases is also crucial for GPC3 inhibition of Hh signaling (56). Low-density-lipoprotein receptor-related protein-1 (LRP1) was also shown to mediate endocytosis of the GPC3-Hh complex (57) (Figure 2B).…”

Section: Gpc3 Wnt and Hedgehog Signalingmentioning

confidence: 99%

The Role of Glypican-3 in Regulating Wnt, YAP, and Hedgehog in Liver Cancer

Kolluri

2019

Front. Oncol.

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Glypican-3 (GPC3) is a cell-surface glycoprotein consisting of heparan sulfate glycosaminoglycan chains and an inner protein core. It has important functions in cellular signaling including cell growth, embryogenesis, and differentiation. GPC3 has been linked to hepatocellular carcinoma and a few other cancers, however, the mechanistic role of GPC3 in cancer development remains elusive. Recent breakthroughs including the structural modeling of GPC3 and GPC3–Wnt complexes represent important steps toward deciphering the molecular mechanism of action for GPC3 and how it may regulate cancer signaling and tumor growth. A full understanding of the molecular basis of GPC3-mediated signaling requires elucidation of the dynamics of partner receptors, transducer complexes, and downstream players. Herein, we summarize current insights into the role of GPC3 in regulating cancer development through Wnt and other signaling pathways, including YAP and hedgehog cascades. We also highlight the growing body of work which underlies deciphering how GPC3 is a key player in liver oncogenesis.

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“…Furthermore, levels of GPC3 in blood differ across reports, with values ranging from several pg/ml to several µg/ml (12,15,(19)(20)(21)(22). Although the roles of GPC3 and its physiological significance have not yet been elucidated, it is thought to relate to the regulation of cell differentiation and proliferation and to exert these functions only after being cleaved and configured into the full-length form by the disulfide bond between N-and C-terminal domains (13,23).…”

Section: Introductionmentioning

confidence: 99%

Usefulness of plasma full‑length glypican‑3 as a predictive marker of hepatocellular carcinoma recurrence after radial surgery

Miura

Fujinami²,

Shimizu³

et al. 2020

Oncol Lett

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Predicting the risk of hepatocellular carcinoma (HCC) recurrence before treatment is necessary for developing subsequent treatment policies. Several tumor markers found in blood, such as alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), are presently used to determine the occurrence and recurrence of HCC and to predict patient prognosis. However, these markers are insufficient for these purposes as certain patients have HCC recurrence despite exhibiting negative AFP and PIVKA-II. The present study identified glypican-3 (GPC3), an embryonal carcinoma antigen that is expressed specifically in HCC and is secreted into blood. Although the N-terminal domain of GPC3 in sera may be a potential prognostic factor for HCC, its biological role remains unclear. By contrast, full-length GPC3 (FL-GPC3) is reported to serve important roles in cell differentiation, proliferation and signaling events that cause HCC. Given the biological roles of FL-GPC3 in HCC progression, the present study evaluated its potential as a predictive marker of HCC recurrence. In the present study, a novel measurement system was constructed to specifically measure plasma FL-GPC3. Subsequently, its ability to predict recurrence after radical surgery in 39 HCC patients was evaluated. The results revealed that preoperative FL-GPC3 levels in patients with recurrence were significantly higher than those in patients without recurrence, suggesting that FL-GPC3 could be a better predictive maker of risk of recurrence than AFP or PIVKA-II. Furthermore, it was determined that the combination of FL-GPC3, AFP and PIVKA-II could predict recurrence within one year of radical surgery with high sensitivity and specificity. Based on these results, the validation of FL-GPC3 as a predictive marker of HCC recurrence in a larger population is warranted.

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Processing by Convertases Is Required for Glypican-3-induced Inhibition of Hedgehog Signaling

Cited by 29 publications

References 29 publications

Proteoglycan form and function: A comprehensive nomenclature of proteoglycans

Proteoglycan form and function: A comprehensive nomenclature of proteoglycans

The Role of Glypican-3 in Regulating Wnt, YAP, and Hedgehog in Liver Cancer

Usefulness of plasma full‑length glypican‑3 as a predictive marker of hepatocellular carcinoma recurrence after radial surgery

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