Author(s): Heinz Ruffner 1 , * , Joëlle Sprunger 1 , Olga Charlat 2 , Juliet Leighton-Davies 1 , Bianka Grosshans 1 , Adrian Salathe 1 , Svenja Zietzling 1 , Valérie Beck 1 , Maxime Therier 1 , Andrea Isken 1 , Yang Xie 2 , Yue Zhang 2 , Huaixiang Hao 2 , Xiaoying Shi 2 , Dong Liu 2 , Qinhui Song 2 , Ieuan Clay 1 , Gabriele Hintzen 1 , Jan Tchorz 1 , Laure C. Bouchez 1 , Gregory Michaud 2 , Peter Finan 2 , Vic E. Myer 2 , Tewis Bouwmeester 1 , Jeff Porter 2 , Marc Hild 2 , Fred Bassilana 1 , Christian N. Parker 1 , Feng Cong 2 , *
The evolutionary conserved Wnt/[beta]-catenin signaling pathway regulates diverse biological processes during embryonic development and adult tissue homeostasis. Defects in Wnt signaling have been linked to many diseases such as cancer, bone disorders, diabetes and neurodegenerative diseases . The main output of Wnt signaling is to regulate the stability of [beta]-catenin. In the absence of Wnt, [beta]-catenin is associated with the multiprotein [beta]-catenin destruction complex that consists of Axin, adenomatous polyposis coli (APC), and glycogen synthase kinase 3 (GSK3). In this complex, [beta]-catenin is constitutively phosphorylated by GSK3 which triggers the binding by beta-transducin repeat containing protein ([beta]-TrCP) and subsequent degradation through the ubiquitin-proteasome pathway. The Wnt signal is received by Frizzled and the low-density lipoprotein receptor related protein 5/6 (LRP5/6). Wnt binding induces phosphorylation of LRP5/6, and phosphorylated LRP5/6 binds to Axin, which leads to the dissociation of the [beta]-catenin destruction complex. Stabilized [beta]-catenin enters the nucleus, binds to the TCF transcription factors and initiates transcription of Wnt responsive genes , .
RSPO proteins are a family of secreted molecules that strongly potentiate Wnt/[beta]-catenin signaling. There are four members of the RSPO family of proteins in vertebrates (RSPO1-4), and all four RSPO proteins stimulate Wnt signaling . Xenopus RSPO2 was identified through cDNA expression cloning for its ability to activate the [beta]-catenin/TCF reporter . Mouse RSPO1 was shown to stimulate the proliferation of intestinal epithelia cells upon overexpression in a transgenic mouse model . In both mice and Xenopus , RSPO proteins are often coexpressed with Wnt proteins and their expression is often activated by Wnt , , . These observations suggest that RSPO may promote Wnt signaling by a positive feedback loop.
RSPO proteins contain two N-terminal furin-like, cysteine-rich domains, followed by a C-terminal thrombospondin domain. It has been shown that the furin-like domains are required and sufficient for activation of Wnt/[beta]-catenin signaling . RSPO proteins function as stem cell growth factors and thus have therapeutic potential in regenerative medicine , , . RSPO1 is able to protect mice from chemotherapy-induced intestinal and oral mucositis in mice . Despite the biological and therapeutic significance of RSPO the exact mechanism of RSPO-induced [beta]-catenin activation is not well understood. It has been postulated that RSPO binds to Kremen and blocks DKK1-induced internalization of LRP6 . However, this observation...