Signaling at the Crossroads: Matrix-Derived Proteoglycan and Reactive Oxygen Species Signaling

Nastase, Madalina-Viviana; Janicova, Andrea; Wygrecka, Małgorzata; Schaefer, Liliana

doi:10.1089/ars.2017.7165

Cited by 34 publications

(41 citation statements)

References 195 publications

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“…Finally, CD44 associates with EMT-related transcription factors, e.g., the Wnt signaling pathway via CD44-associated LRP6 (LDL receptor related protein6) (Xu et al, 2015). Of central importance for the engagement of CD44 as a CIC marker are the associations with non-RTK (Cooper and Qian, 2008; Nastase et al, 2017), which can proceed via activated RTK, GPCR, cytoskeletal linker proteins, or directly via GEM-recruited CD44v (Ingley, 2008; Ekyalongo et al, 2015; Korcsmaros et al, 2017). …”

Section: Introductionmentioning

confidence: 99%

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

Wang

Zhao

Hackert

et al. 2018

Front. Cell Dev. Biol.

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Metastasis is the leading cause of cancer death, tumor progression proceeding through emigration from the primary tumor, gaining access to the circulation, leaving the circulation, settling in distant organs and growing in the foreign environment. The capacity of a tumor to metastasize relies on a small subpopulation of cells in the primary tumor, so called cancer-initiating cells (CIC). CIC are characterized by sets of markers, mostly membrane anchored adhesion molecules, CD44v6 being the most frequently recovered marker. Knockdown and knockout models accompanied by loss of tumor progression despite unaltered primary tumor growth unraveled that these markers are indispensable for CIC. The unexpected contribution of marker molecules to CIC-related activities prompted research on underlying molecular mechanisms. This review outlines the contribution of CD44, particularly CD44v6 to CIC activities. A first focus is given to the impact of CD44/CD44v6 to inherent CIC features, including the crosstalk with the niche, apoptosis-resistance, and epithelial mesenchymal transition. Following the steps of the metastatic cascade, we report on supporting activities of CD44/CD44v6 in migration and invasion. These CD44/CD44v6 activities rely on the association with membrane-integrated and cytosolic signaling molecules and proteases and transcriptional regulation. They are not restricted to, but most pronounced in CIC and are tightly regulated by feedback loops. Finally, we discuss on the engagement of CD44/CD44v6 in exosome biogenesis, loading and delivery. exosomes being the main acteurs in the long-distance crosstalk of CIC with the host. In brief, by supporting the communication with the niche and promoting apoptosis resistance CD44/CD44v6 plays an important role in CIC maintenance. The multifaceted interplay between CD44/CD44v6, signal transducing molecules and proteases facilitates the metastasizing tumor cell journey through the body. By its engagement in exosome biogenesis CD44/CD44v6 contributes to disseminated tumor cell settlement and growth in distant organs. Thus, CD44/CD44v6 likely is the most central CIC biomarker.

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Section: Introductionmentioning

confidence: 99%

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

Wang

Zhao

Hackert

et al. 2018

Front. Cell Dev. Biol.

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“…2C), which is discussed in more detail elsewhere in this Forum (34,81,119,124,128,178). We review the emerging physiological functions of this regulation and the evidence that pathological dysregulation of matricellular protein expression contributes to acute and chronic disease states that are characterized by insufficient NO signaling and/or increased oxidative stress.…”

Section: Fig 1 Matricellular Protein Familiesmentioning

confidence: 99%

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Roberts

Kaur

Isenberg

2017

Antioxidants & Redox Signaling

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Significance: In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors, matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H 2 S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 (TSP1) regulates NO, H 2 S, and superoxide production and signaling in several cell types. The TSP1 receptor CD47 plays a central role in inhibition of NO signaling, but other TSP1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. Critical Issues: Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. Future Directions: Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. Antioxid. Redox Signal. 27, 874-911.

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“…Small leucine‐rich proteoglycans (SLRPs) form a large extracellular matrix (ECM) proteoglycan family consisting of 18 reported members so far . In the last decades the research in the ECM field underlined the functional complexity of certain SLRPs being recognized as dual molecules: tissue organizers and signaling molecules . Biglycan is one of the best characterized signaling SLRP, modulating various pathways dependent on, for example, Toll‐like receptors (TLR)2/4 , transforming growth factor (TGF)‐β1–ALK5 , bone morphogenetic protein (BMP) , or Wnt3a/LRP6 .…”

Section: Introductionmentioning

confidence: 99%

“…In the last decades the research in the ECM field underlined the functional complexity of certain SLRPs being recognized as dual molecules: tissue organizers and signaling Abbreviations apoB, apolipoprotein B; BMP, bone morphogenetic protein; CAVD, calcific aortic valve disease; CCL, chemokine (C-C motif) ligand; CD, cluster of differentiation; CXCL, chemokine (C-X-C motif) ligand; CXCR, chemokine (C-X-C) motif receptor; DAMP, damage-associated molecular pattern; DN, diabetic nephropathy; ECM, extracellular matrix; Erk, extracellular signal-regulated kinase; GAG, glycosaminoglycan; HSP, heat shock protein; IL, interleukin; IRI, ischemia/reperfusion injury; LDL, low-density lipoprotein; LN, lupus nephritis; MyD88, adaptor molecule myeloid differentiation primary response gene 88; NF-jB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOX, NADPH oxidase; SLRP, small leucine-rich proteoglycan; TGF-b, transforming growth factor-b; TLR, Toll-like receptors; TNF-a, tumor necrosis factor alpha; TRIF, TIR domain-containing adapter inducing interferon-b; VICs, valve interstitial cells. molecules [1][2][3][4]. Biglycan is one of the best characterized signaling SLRP, modulating various pathways dependent on, for example, Toll-like receptors (TLR) 2/4 [5], transforming growth factor (TGF)-b1-ALK5 [6], bone morphogenetic protein (BMP) [7][8][9], or Wnt3a/LRP6 [10].…”

Section: Introductionmentioning

confidence: 99%

Breaking down chronic inflammatory diseases: the role of biglycan in promoting a switch between inflammation and autophagy

et al. 2019

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It is well established that biglycan, a small leucine‐rich proteoglycan, acts as an extracellular matrix‐derived danger signal in its soluble form. By binding to innate immunity Toll‐like receptors (TLR) 2 and 4, biglycan initiates and perpetuates the inflammatory response. Previous work has conveyed that biglycan's role in inflammation extends far beyond its function as a canonical danger signal. It has been shown that biglycan acts in an anti‐inflammatory capacity, wherein it tightly regulates the inflammatory response. In this review, we will discuss a paradigm shift to our understanding of biglycan signaling in inflammation. Mounting evidence suggests that the selective interactions between biglycan, TLRs, and their adapter proteins critically regulate downstream signaling and disease outcome. Biglycan can act as a high‐affinity ligand for TLR coreceptors CD14 and CD44, further providing an additional layer of complexity. We propose a novel concept, that biglycan steers signaling toward inflammation by interacting with CD14, whereas it can trigger autophagy by binding to CD44. Thus, biglycan, and perhaps others soluble proteoglycans, could function as molecular switches which could either propagate the signaling of chronic inflammation or promote the resolution of inflammatory processes. Obviously, these new functions have broad implications in the regulation of various inflammatory diseases and could provide the basis for developing novel therapeutic regimens that would selectively target the interactions between biglycan, TLRs, coreceptors, and adapter molecules.

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Signaling at the Crossroads: Matrix-Derived Proteoglycan and Reactive Oxygen Species Signaling

Abstract: As we become more and more aware of the interactions between PG and ROS signaling underlying intracellular communication and cell fate decisions, it is quite conceivable that this field will allow to identify new therapeutic targets.-Antioxid. Redox Signal. 27, 855-873.

Cited by 34 publications

References 195 publications

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Breaking down chronic inflammatory diseases: the role of biglycan in promoting a switch between inflammation and autophagy

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