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.

Figure 1

Decorin interacts with several receptor tyrosine kinases for the control of fundamental cellular behaviors in normal and malignant circumstances. Schematic representation of cell surface receptor tyrosine kinases occupied by decorin. Biological consequences of binding and resultant signal transduction are outlined below the appropriate receptor. Please refer to the text for additional information.

Figure 2

Biglycan and decorin bind innate immune system receptors for immunoregulation and tumorigenesis. The innate immune receptors TLR2, TLR4 and the purinergic P2X_7/4 provide novel signaling circuits through which biglycan and decorin bind for regulating the innate immune system and cultivating a pro-inflammatory environment in sepsis and tumorigenesis. Biglycan also binds LRP6 for tumor promotion. Please refer to the text for more information.

Figure 3

Basement membrane heparan sulfate proteoglycans ligate multiple receptors for effector function in a variety of cells and tissues. Graphical description of the C-terminal domains of the major basement membrane HSPGs demonstrating modular organization and architecture (left) and a summary of the primary receptors engaged (right). Figure adapted from Iozzo et al .