Biological functions of the small leucine-rich proteoglycans: from genetics to signal transduction

Abstract

The small leucine-rich proteoglycan (SLRP) family has significantly expanded in the past decade to now encompass five discrete classes, grouped by common structural and functional properties. Some of these gene products are not classical proteoglycans, whereas others have new and unique features. In addition to being structural proteins, SLRPs constitute a network of signal regulation: being mostly extracellular, they are upstream of multiple signaling cascades. They affect intracellular phosphorylation, a major conduit of information for cellular responses, and modulate distinct pathways, including those driven by bone morphogenetic protein/transforming growth factor beta superfamily members, receptor tyrosine kinases such as ErbB family members and the insulin-like growth factor I receptor, and Toll-like receptors. The wealth of mechanistic insights into the molecular and cellular functions of SLRPs has revealed both the sophistication of this family of regulatory proteins and the challenges that remain in uncovering the totality of their functions. This review is focused on novel biological functions of SLRPs with special emphasis on their protein cores, newly described genetic diseases, and signaling events in which SLRPs play key functions.

FIGURE 1.

Phylogenetic analysis and chromosomal organization of various human SLRP classes. The color-coded dendrogram (left) shows the presence of five distinct families of SLRP and related LRR proteins. The consensus for the N-terminal Cys-rich cluster is also shown. The chromosomal arrangement of the various SLRP genes is shown in a telomeric orientation (right). Transcriptional direction is shown by the arrows above the color-coded boxes. The horizontal distance between genes is not to scale. This figure was modified after Henry et al. (7). Sequences were retrieved from Swiss-Prot and inserted into Jalview 2.3, and the rooted dendrogram was generated with the ClustalW2 algorithm and plotted with Biology Workbench 3.2 DRAWGRAM.

FIGURE 2.

Multiple signaling pathways evoked by SLRPs. Several distinct pathways are affected by various SLRPs as indicated. The diagram is obviously incomplete insofar as it does not include cross-talks among the various signal transduction pathways. For additional information, see text. PI3K, phosphatidylinositol 3-kinase; PKB, protein kinase B.