Proteoglycans in health and disease: novel regulatory signaling mechanisms evoked by the small leucine‐rich proteoglycans

Abstract

The small leucine‐rich proteoglycans (SLRPs) are involved in many aspects of mammalian biology, both in health and disease. They are now being recognized as key signaling molecules with an expanding repertoire of molecular interactions affecting not only growth factors, but also various receptors involved in controlling cell growth, morphogenesis and immunity. The complexity of SLRP signaling and the multitude of affected signaling pathways can be reconciled with a hierarchical affinity‐based interaction of various SLRPs in a cell‐ and tissue‐specific context. Here, we review this interacting network, describe new relationships of the SLRPs with tyrosine kinase and Toll‐like receptors and critically assess their roles in cancer and innate immunity.

A comparative evaluation of the small leucine-rich proteoglycans of pathological human intervertebral discs

“…Decorin, biglycan, fibromodulin and lumican interact with many other matrix components other than the fibrillar collagens, including types VI, XII and XIV collagens, fibronectin, elastin, in addition to growth factors and cytokines such as EGF, TGFb and TNFa [3,13,16,23]. The GAG chains of the SLRPs provide them with their growth factor binding properties through which they can sequester these in the extracellular matrix.…”

“…The GAG chains of the SLRPs provide them with their growth factor binding properties through which they can sequester these in the extracellular matrix. The SLRPs have diverse functions as modulators of tissue organization, cellular proliferation, matrix adhesion, and the cellular responses to growth factors and cytokines [13,16,23]. This family of proteoglycans have emerging roles in mammalian biology in health and disease and are now recognised as key signalling molecules with growth factors and a number of receptors which regulate cell growth, morphogenesis and immunity [13,16,23,27].…”

Small leucine-rich proteoglycans orchestrate receptor crosstalk during inflammation

“…25,26 Several matrix proteoglycans contain LRR motifs in their protein core. 27 The relatively small size of the protein core (up to 42 kDa) is another hallmark of this class of proteoglycans, explaining why these compounds are referred to as small leucine-rich proteoglycans. 18,[28][29][30] SLRPs are covalently substituted with glycosaminoglycan (GAG) side chains: chondroitin sulfate, dermatan sulfate or keratan sulfate.…”

Decorin causes autophagy in endothelial cells via Peg3

“…5A) to VEGFR2 ectodomain Ig [1][2][3][4][5][6][7] . Moreover, immobilized decorin bound with similar affinity to soluble VEGFR2 Ig [1][2][3][4][5][6][7] (Fig. 5B), and its binding to VEGFR2 could be displaced efficiently by VEGFA (IC 50 ∼50 nM) (Fig.…”

“…Many SLRPs, including decorin and biglycan, regulate a variety of vital biological processes, especially via their innate ability to bind collagen type I and ultimately regulate fibrillogenesis and bioavailability of various growth factors (3). However, many recent studies have broadened our view of decorin from a specialized collagen-bound factor and regulator of matrix assembly to that of a soluble multifunctional signaling proteoglycan (4,5). For example, circulating decorin has been detected in the plasma of normal volunteers and found to be elevated in diabetic (6) and septic patients (7).…”