3.5 Small leucine-rich proteoglycans: multifunctional signaling effectors

Merline, Rosetta; Nastase, Madalina V.; Iozzo, Renato V.; Schaefer, Liliana

doi:10.1515/9783110258776.185

Cited by 13 publications

(21 citation statements)

References 80 publications

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“…This binding subsequently promotes receptor dimerization, analogous to the natural ligand EGF [112], followed by a rapid and transient phosphorylation of the unstructured intracellular tails. This is followed by recruitment and activation of downstream effectors, caveosome-mediated internalization of the decorin/receptor complex, and eventual lysosomal degradation [9,14,113,114]. The latter causes a protracted cessation of intracellular receptor signaling.…”

Section: Suppression Of Growth and Tumor Angiogenesis Via Egfr Andmentioning

confidence: 99%

Decorin as a multivalent therapeutic agent against cancer

Neill

Schaefer

Iozzo

2016

Advanced Drug Delivery Reviews

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112

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Decorin is a prototypical small leucine-rich proteoglycan and epitomizes the multifunctional nature of this critical gene family. Soluble decorin engages multiple receptor tyrosine kinases within the target rich environment of the tumor stroma and tumor parenchyma. Upon receptor binding, decorin initiates signaling pathways within endothelial cells downstream of VEGFR2 that ultimately culminate in a Peg3/Beclin 1/LC3-dependent autophagic program. Concomitant with autophagic induction, decorin blunts capillary morphogenesis and endothelial cell migration, thereby significantly compromising tumor angiogenesis. In parallel within the tumor proper, decorin binds multiple RTKs with high affinity, including Met, for a multitude of oncosuppressive functions including growth inhibition, tumor cell mitophagy, and angiostasis. Decorin is also pro-inflammatory by modulating macrophage function and cytokine secretion. Decorin suppresses tumorigenic growth, angiogenesis, and prevents metastatic lesions in a variety of in vitro and in vivo tumor models. Therefore, decorin would be an ideal therapeutic candidate for combatting solid malignancies.

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Section: Suppression Of Growth and Tumor Angiogenesis Via Egfr Andmentioning

confidence: 99%

Decorin as a multivalent therapeutic agent against cancer

Neill

Schaefer

Iozzo

2016

Advanced Drug Delivery Reviews

Self Cite

112

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“…This initiates a pro-inflammatory cascade that converges on NF-κB and evokes the synthesis and development of mature IL-1β 96 , and release of TNF-α and IL-6. Mechanistically, biglycan promotes receptor clustering and cooperativity of TLR2/4 with the purinergic P2X 7 /P2X 4 receptors (Figure 2) 5,9,96 . This affords rapid generation of reactive oxygen species that is directly involved in activating the NLRP3/ASC inflammasome 96 .…”

Section: Biglycan Links Soluble Matrix With Innate Immune Responses Vmentioning

confidence: 99%

“…Several lines of evidence have converged on the concept that decorin may also be involved in regulating immunological responses in a manner congruent with biglycan 5,104 . Decorin suppresses TGF-β, thereby repressing the macrophage phenotype via p27 Kip1 and p21 WAF1 induction 105 , promotes synthesis of the potent chemoattractant MCP-1 106 , and potentiates IFN-γ for allergen-induced inflammation 107 .…”

Section: Decorin Fosters a Pro-inflammatory Signature Via Tlr2/4mentioning

confidence: 99%

“…The original discovery that soluble, monomeric decorin 11 is capable of binding EGFR and communicating with the intracellular signaling apparatus via cell surface signaling receptors 12 pioneered the paradigm-changing concept that matrix components embody a critical regulatory network 5,13–17 . Following this initial discovery, decorin emerged as the leading candidate for a matrix-derived repressor of tumorigenic growth with inherent angiostatic and pro-autophagic activities 18–20 that wholly manifests from RTK partial agonism.…”

Section: Introductionmentioning

confidence: 99%

“…For example, both circulating biglycan and decorin have been implicated in regulating innate inflammatory responses downstream of TLR2/4 (see below) 5,9,32–34 . Biomechanically, decorin and biglycan also share overlapping functions in the mechanobiology of tendon structure 35–37 , and have distinct roles in fetal membrane signaling 38 .…”

Section: Introductionmentioning

confidence: 99%

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Decoding the Matrix: Instructive Roles of Proteoglycan Receptors

2015

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The extracellular matrix is a dynamic repository harboring instructive cues that embody substantial regulatory dominance over many evolutionarily conserved intracellular activities including proliferation, apoptosis, migration, motility, and autophagy. The matrix also coordinates and parses hierarchical information, such as angiogenesis, tumorigenesis, and immunological responses, typically providing the critical determinants driving each outcome. We provide the first comprehensive review focused on proteoglycan receptors, that is, signaling transmembrane proteins that use secreted proteoglycans as ligands, in addition to their natural ligands. The majority of these receptors belong to an exclusive subset of receptor tyrosine kinases and assorted cell surface receptors that specifically bind, transduce, and modulate fundamental cellular processes following interactions with proteoglycans. The class of small leucine-rich proteoglycans is the most studied so far, and constitutes the best understood example of proteoglycan/receptor interactions. Decorin and biglycan evoke autophagy and immunological responses that deter, suppress, or exacerbate pathological conditions such as tumorigenesis, angiogenesis, and chronic inflammatory disease. Basement membrane-associated heparan sulfate proteoglycans - perlecan, agrin and collagen XVIII - represent a unique cohort and provide proteolytically-cleaved bioactive fragments for modulating cellular behavior. The receptors that bind the genuinely multifactorial and multivalent proteoglycans represent a nexus in understanding basic biological pathways and opens new avenues for therapeutic and pharmacological intervention.

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De novo expression of circulating biglycan evokes an innate inflammatory tissue response via MyD88/TRIF pathways

et al. 2014

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Matrix-bound constituents, such as the small leucine-rich proteoglycan biglycan, can act as powerful signaling molecules when released by limited proteolysis of the extracellular matrix or de novo synthesized by macrophages in the circulation and body fluids. Specifically, biglycan acts as an endogenous ligand of innate immunity by directly engaging the Toll-like receptor (TLR)-2 and -4. In this study, we generated a transient transgenic mouse model where biglycan was de novo overproduced by hepatocytes driven by the albumin promoter. Transgenic biglycan was rapidly and abundantly synthesized by hepatocytes and released into the bloodstream. Notably, we found that circulating biglycan accumulated in the kidneys where it caused recruitment of leukocytes infiltrating the renal parenchyma concurrent with abnormal renal levels of chemoattractants CXCL1, CXCL2, CCL2 and CCL5. Using mice deficient in either TLR adapter proteins MyD88 or TRIF we discovered that MyD88 deficiency drastically reduced neutrophil and macrophage infiltration in the kidney, whereas TRIF deficiency decreased T cell infiltrates. Production of CXCL1, CXCL2 and CCL2 required MyD88, whereas the levels of T cell and macrophage attractant CCL5 required TRIF. Thus, we provide robust genetic evidence for circulating biglycan as a powerful pro-inflammatory mediator targeting the renal parenchyma. Furthermore, our results provide the first evidence that biglycan differentially triggers chemoattraction of leukocytes via two independent pathways, both under the control of TLR2/4, utilizing either MyD88 or TRIF adaptor proteins. As aberrant expression of biglycan occurs in several inflammatory diseases, this transient transgenic mouse model could serve as a valuable research tool in investigating the effects of increased biglycan expression in vivo and for the development of therapeutic strategies in the treatment of inflammatory diseases.

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3.5 Small leucine-rich proteoglycans: multifunctional signaling effectors

Cited by 13 publications

References 80 publications

Decorin as a multivalent therapeutic agent against cancer

Decorin as a multivalent therapeutic agent against cancer

Decoding the Matrix: Instructive Roles of Proteoglycan Receptors

De novo expression of circulating biglycan evokes an innate inflammatory tissue response via MyD88/TRIF pathways

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