The R-spondin family of proteins: Emerging regulators of WNT signaling

Abstract

Recently, the R-spondin (RSPO) family of proteins has emerged as important regulators of WNT signaling. Considering the wide spectrum of WNT signaling functions in normal biological processes and disease conditions, there has been a significantly growing interest in understanding the functional roles of RSPOs in multiple biological processes and determining the molecular mechanisms by which RSPOs regulate the WNT signaling pathway. Recent advances in the RSPO research field revealed some of the in vivo functions of RSPOs and provided new information regarding the mechanistic roles of RSPO activity in regulation of WNT signaling. Herein, we review recent progress in RSPO research with an emphasis on signaling mechanisms and biological functions.

The Wnt Signalling Pathways: A Short Review and Specific Roles in Bone Biochemistry

“…The proteins of the R-spondins (RSPO) family have 234 to 272 amino acids and present the following domains in their structure: an N-terminal putative signal sequence for secretion, a thrombospondin type I repeat (TSR) domain, a variable length domain, rich in basic amino acids and a furine-like CRD. RSPOs are also considered as Wnt agonists, as they activate the β-catenin signalling pathway, however RSPOs may have different receptors as Wnts [17]. Recently, the presence of leucine-rich repeat containing Gprotein-coupled receptors (LGR) has been described.…”

Intrinsic disorder in spondins and some of their interacting partners

“…[32][33][34][35][36][37][38][39][40] These proteins have molecular masses of approximately 35 kDa and are characterized by the presence of 2 N-terminal furin-like repeats, which are necessary for Wnt signaling. R-spondins can enhance responses to low-dose Wnt protein and also serves as activators of a canonical Wnt signaling pathway, where they act as ligands for the LGR4-6 receptors.…”

“…They are found in eukaryotic organisms and are grouped into different families, such as the R-spondin, the subcommissural organ (SCO)-spondin, the M-spondin (mindin), and the F-spondin. Spondins are engaged in various vital biological functions, such as regulators of Wnt signaling (R-spondins), [32][33][34][35][36][37][38][39][40] regulation of the developing skeleton, limb formation, and the maintenance of adult bone mass (R-spondins), 39,41 regulation of stem cells (R-spondin), 37,42,43 neuron/ glia interaction and neuronal differentiation and development (SCO-spondin), 44,45 interaction with the b-amyloid precursor protein (APP) and its controlled proteolysis (F-spondin), 46,47 regulation of the accurate path-finding of embryonic axons (F-spondin), 48 and promotion of the neurite outgrowth and inhibition of the angiogenesis (F-spondin and mindin). 48 Being the members of the TSP family, these proteins have complex modular structures.…”

How rare bone diseases have informed our knowledge of complex diseases

“…LGR4 binds the R-spondin family of proteins that are known to potentiate Wnt/b-catenin signaling (see review 78 ). Zhu et al 79 have shown that LGR4 is a key receptor for R-spondin 2.…”