title: Decoding the Matrix: Instructive Roles of Proteoglycan Receptors.
abstract: 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 open new avenues for therapeutic and pharmacological intervention.
authors.affiliation: †Department of Pathology, Anatomy and Cell Biology and Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Neill
authors.affiliation: ‡Department of Pharmacology, Goethe University, 60590 Frankfurt, Germany.
authors.forename: Liliana
authors.initials: L
authors.lastname: Schaefer
authors.affiliation: †Department of Pathology, Anatomy and Cell Biology and Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, United States.
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
mesh_terms: D000818:Animals; D001343:Autophagy / Q000276:immunology*; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000378:metabolism; D005109:Extracellular Matrix / Q000276:immunology / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism; D011509:Proteoglycans / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D011956:Receptors, Cell Surface