A Novel Modulatory Mechanism of Transforming Growth Factor-β Signaling through Decorin and LRP-1

Cabello-Verrugio, Claudio; Brandan, Enrique

doi:10.1074/jbc.m700243200

Cited by 114 publications

(91 citation statements)

References 60 publications

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“…Decorin, with a similar structure to ASPN, is a multifunctional molecule of the ECM (33). Previous evidence suggests that decorin, as a key component of the tumor stroma, interacts with various growth factors such as EGF and TGF-β and is necessary for cell migration (34,35).…”

Section: Discussionmentioning

confidence: 99%

Asporin participates in gastric cancer cell growth and migration by influencing EGF receptor signaling

2015

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Abstract. Asporin (ASPN), a novel member of the small leucine-rich proteoglycan (SLRP) family, serves as a key component of the tumor stroma and has been reported to be abnormally expressed in certain types of tumors. Specifically, the proteoglycan was proven to activate the coordinated invasion of scirrhous gastric cancer and cancer-associated fibroblasts. However, the role of ASPN in cancer cell growth and metastasis has not yet been addressed. In the present study, we aimed to evaluate the tumoricidal benefits of ASPN on tumorigenesis and progression of gastric cancer. Firstly, it was demonstrated that ASPN was overexpressed in gastric carcinoma tissues when compared to the corresponding non-cancerous tissues, and it had varied levels of expression in gastric cancer epithelial cell lines. Additionally, we assessed the effects of transient siRNA-mediated ASPN knockdown on gastric cancer cells. ASPN silencing inhibited proliferation and suppressed the migration of immortalized neoplastic epithelial cells. Furthermore, at the molecular level, we found that downregulation of ASPN blocked the anti-apoptotic molecule Bcl-2, increased the expression of pro-apoptotic molecule Bad, reduced the expression of migration-related proteins CD44 and matrix metalloproteinase (MMP)-2, and abrogated the activation of the phosphorylation status of ERK and epidermal growth factor (EGF) and its receptor (EGFR). Collectively, our findings indicate that ASPN is upregulated and plays an oncogenic role in gastric cancer progression and metastasis by influencing the EGFR signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Asporin participates in gastric cancer cell growth and migration by influencing EGF receptor signaling

2015

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“…A tissue-specific regulation of TGFβ/BMP signaling by SLRPs may be indirect, via local variations in other modifiers of the signaling pathway. For example, in myoblasts, the interaction of Dcn with lipoproteinreceptor-related protein 1 (LRP-1) modulates TGFβ activity (Cabello-Verrugio and Brandan, 2007). Additionally, the Asp variant (D14-PLAP-1) has stronger affinity to BMP2 to repress its activity compared with other variants (Kajikawa et al, 2014) in PDL cells.…”

Section: Fmod and Bgn Regulate Tgfβ/bmp Signaling In The Pdlmentioning

confidence: 99%

“…SLRP family members have been shown to modify TGFβ/BMP bioavailability and/or function by binding to and sequestering TGFβ/BMPs within the ECM (Schaefer and Schaefer, 2010). Fmod, Bgn, Asp, and Dcn are capable of binding to members of the TGFβ superfamily and thereby regulate their activity (Hildebrand et al, 1994;Cabello-Verrugio and Brandan, 2007;Kajikawa et al, 2014). Additionally, Bgn enhances the binding of BMP4 to its inhibitory effectors, effectively reducing BMP4 signaling during the early embryonic development of xenopus (Moreno et al, 2005).…”

Section: Fmod and Bgn Regulate Tgfβ/bmp Signaling In The Pdlmentioning

confidence: 99%

Fibromodulin and Biglycan Modulate Periodontium through TGFβ/BMP Signaling

et al. 2014

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A full understanding of the key regulators controlling periodontal development and homeostasis is necessary for the design of improved periodontal regenerative therapies. Small leucinerich proteoglycans (SLRPs) are extracellular matrix molecules suggested to regulate collagen organization and cell signaling. Mice with double-deficiency of 2 SLRPs, fibromodulin and biglycan (dKO), acquire skeletal abnormalities, but their roles in regulating the periodontium remain undefined and were the focus of our studies. Transmission electron microscopy studies showed abnormal collagen fibrils in the periodontal ligament (PDL) and altered remodeling of alveolar bone in dKO mice. Immunohistochemistry (IHC) revealed increased staining of SLRPs (asporin, lumican, and decorin) and dentin matrix protein-1 (DMP1, a mechanosensory/osteocyte marker), while osteoblast markers, bone sialoprotein and osteopontin, remained unchanged. Disruption of homeostasis was further evidenced by increased expression of receptor-activator of nuclear factor-κB ligand (RANKL) and elevated numbers of osteoclasts, especially noted around the alveolar bone of molars (buccal side) and incisors. Polymerase chain reaction (PCR) array revealed hyperactive transforming growth factors beta/bone morphogenetic protein (TGFβ/BMP) signaling in dKO PDL tissues, which was further confirmed by elevated expression of phosphorylated Smad5 (p-Smad5) by IHC in dKO PDL. These studies highlight the importance of SLRPs in maintaining periodontal homeostasis through regulation of TGFβ/BMP signaling, matrix turnover, and collagen organization.

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“…LRP1 has been shown to affect the signaling of TGF-␤ in Chinese hamster ovary (CHO) cells, where LRP1-deficient CHO cells gained resistance toward TGF-␤-induced cell growth arrest (34). Many other groups have also demonstrated the importance of LRP1 in TGF-␤ signaling events (35)(36)(37)(38)(39). These were important observations demonstrating that LRP1 facilitates TGF-␤ signaling because LRP1 was only originally classified as a scavenger receptor facilitating degradation through receptor-mediated ligand endocytosis (40).…”

mentioning

confidence: 99%

Engulfment Protein GULP Is Regulator of Transforming Growth Factor-β Response in Ovarian Cells

Cheng

Martin

et al. 2012

Journal of Biological Chemistry

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Background:The low density lipoprotein receptor-related protein 1 (LRP1) is a transforming growth factor ␤ (TGF-␤) receptor in ovarian cells. Results: GULP is an adapter to LRP1 and mediates TGF-␤ signaling in signaling-competent early endosomes. Conclusion: GULP positively regulates TGF-␤ signaling in ovarian cells. Significance: GULP is poorly expressed in ovarian cancer cells and is a target for TGF-␤-mediated growth inhibition.

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A Novel Modulatory Mechanism of Transforming Growth Factor-β Signaling through Decorin and LRP-1

Abstract: Transforming growth factor-␤ (TGF-␤

Cited by 114 publications

References 60 publications

Asporin participates in gastric cancer cell growth and migration by influencing EGF receptor signaling

Asporin participates in gastric cancer cell growth and migration by influencing EGF receptor signaling

Fibromodulin and Biglycan Modulate Periodontium through TGFβ/BMP Signaling

Engulfment Protein GULP Is Regulator of Transforming Growth Factor-β Response in Ovarian Cells

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