The matricellular functions of small leucine-rich proteoglycans (SLRPs)

Abstract

The small leucine-rich proteoglycans (SLRPs) are biologically active components of the extracellular matrix (ECM), consisting of a protein core with leucine rich-repeat (LRR) motifs covalently linked to glycosaminoglycan (GAG) side chains. The diversity in composition resulting from the various combinations of protein cores substituted with one or more GAG chains along with their pericellular localization enables SLRPs to interact with a host of different cell surface receptors, cytokines, growth factors, and other ECM components, leading to modulation of cellular functions. SLRPs are capable of binding to: (i) different types of collagens, thereby regulating fibril assembly, organization, and degradation; (ii) Toll-like receptors (TLRs), complement C1q, and tumor necrosis factor-alpha (TNFalpha), regulating innate immunity and inflammation; (iii) epidermal growth factor receptor (EGF-R), insulin-like growth factor receptor (IGF-IR), and c-Met, influencing cellular proliferation, survival, adhesion, migration, tumor growth and metastasis as well as synthesis of other ECM components; (iv) low-density lipoprotein receptor-related protein (LRP-1) and TGF-beta, modulating cytokine activity and fibrogenesis; and (v) growth factors such as bone morphogenic protein (BMP-4) and Wnt-I-induced secreted protein-1 (WISP-1), controlling cell proliferation and differentiation. Thus, the ability of SLRPs, as ECM components, to directly or indirectly regulate cell-matrix crosstalk, resulting in the modulation of various biological processes, aptly qualifies these compounds as matricellular proteins.

Fig. 1

Cell type-specific functions mediated by decorin via modulation of IGF-IR signaling. Decorin binds and induces phosphorylation of the insulin-like growth factor-I (IGF-I) receptor, causing downstream activation of phosphoinositide-3 kinase (PI3K) and the Akt/protein kinase B (Akt/PKB) pathway. In endothelial and renal tubular epithelial cells this signaling cascade leads to an inhibition of apoptosis, whereas in renal fibroblasts signaling through mammalian target of rapamycin (mTOR) and p70S6 Kinase (p70S6K) leads to increased translation and synthesis of fibrillin-1. These pathways demonstrate the intricate regulatory mechanisms whereby decorin modulates IGF-IR signaling in a cell type-specific manner, thereby giving rise to different biological outcomes