R-spondin signaling as a pivotal regulator of tissue development and homeostasis

Abstract

R-spondins (Rspos) are cysteine-rich secreted glycoproteins which control a variety of cellular functions and are essential for embryonic development and tissue homeostasis. R-spondins (Rspo1 to 4) have high structural similarity and share 60% sequence homology. It has been shown that their cysteine-rich furin-like (FU) domain and the thrombospondin (TSP) type I repeat domain are essential for initiating downstream signaling cascades and therefore for their biological functions. Although numerous studies have unveiled their pivotal role as critical developmental regulators, the most important finding is that Rspos synergize Wnt signaling. Recent studies have identified novel receptors for Rspos, the Lgr receptors, closely related orphans of the leucin-rich repeat containing G protein-coupled receptors, and proposed that Rspos potentiate canonical Wnt signaling via these receptors. Given that Wnt signaling is one of the most important developmental signaling pathways that controls cell fate decisions and tissue development, growth and homeostasis, Rspos may function as key players for these processes as well as potential therapeutic targets. Here, I recapitulate the Wnt signaling and then outline the biological role of Rspos in tissue development and homeostasis and explore the possibility that Rspos may be used as therapeutic targets.

Prognostic value of immune‐related genes and immune cell infiltration analysis in the tumor microenvironment of head and neck squamous cell carcinoma

“…46 R-spondins (Rspos) are cysteine-rich secreted glycoproteins that control a variety of cellular functions and are identified as direct activators of Wnt/β-catenin signaling. 47 RSPO1, a crucial regulator of canonical β-catenin signaling, could directly activate TGFβ signaling cooperatively with TGFβ type II receptor in colon cancer cells, and enhance TGFβ-mediated growth inhibition and stress-induced apoptosis. 48 RSPO1 was also reported to protect from radiation-induced oral mucositis.…”

“…Furthermore, CCR7 expression levels in human tumors correlate with signatures of CD141(+) DC, intratumor T cells, and better clinical outcomes 46 . R‐spondins (Rspos) are cysteine‐rich secreted glycoproteins that control a variety of cellular functions and are identified as direct activators of Wnt/β‐catenin signaling 47 . RSPO1, a crucial regulator of canonical β‐catenin signaling, could directly activate TGFβ signaling cooperatively with TGFβ type II receptor in colon cancer cells, and enhance TGFβ‐mediated growth inhibition and stress‐induced apoptosis 48 .…”

R-spondin 3 deletion favors Erk phosphorylation to enhance Wnt signaling and bone formation

“…In this context, the fact that several studies have demonstrated that the four Roof plate-specific spondin, R-spondins (Rspo1 to 4), synergize with Wnt ligands to activate Wnt signaling 4,[7][8][9][10][11][12][13] raises the question of their potential role in skeletal development and homeostasis. This enhancement of Wnt activity is attributed to the ability of Rspos to prevent the ubiquitination and degradation of the Lrp5/6/Fzd receptor complex via Lgr4-6, closely related orphans of the leucin-rich repeat containing G protein-coupled receptors, and the transmembrane E3 ubiquitin ligases ring finger 43 (Rnf43) and zinc and ring finger 3 (Znrf3), sensitizing cells to Wnt ligands 7,[14][15][16][17][18] .…”

“…This enhancement of Wnt activity is attributed to the ability of Rspos to prevent the ubiquitination and degradation of the Lrp5/6/Fzd receptor complex via Lgr4-6, closely related orphans of the leucin-rich repeat containing G protein-coupled receptors, and the transmembrane E3 ubiquitin ligases ring finger 43 (Rnf43) and zinc and ring finger 3 (Znrf3), sensitizing cells to Wnt ligands 7,[14][15][16][17][18] . Although the role of Lgr receptors in the effects of Rspos is well established, recent reports have shown that Rspo2 and Rspo3 can also enhance Wnt signaling independently of Lgr receptors, possibly by acting as direct antagonist ligands to RNF43 and ZNRF3 11,19,20 .…”

“…The four Rspos belong to a family of cysteine-rich secreted glycoproteins with high structural similarity and 60% sequence homology 8,11 . Although all Rspos are expressed in bone during development, they appear to have specific functions and their deletion in mice and human leads to different phenotypes 10,13,[24][25][26][27][28][29][30][31] .…”