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The RSpondin (Rspo) protein family is a recently described group of 4 distinct human secreted proteins. Reported activities for RSpo proteins include essential roles in vertebrate development and their ligand-type activities overlap substantially with those of the canonical Wnt ligands in that both RSpo and canonical Wnt signaling result in the activation of β-catenin. In a general functional screen for human secreted proteins using transgenic mouse models, we identified human Rspondin 1 (hRSpo1) protein as a potent and specific mitogen for the gastrointestinal epithelium and demonstrated potential therapeutic applications for the protein in mouse models of cancer therapy-induced mucositis. In contrast to previous studies, our data indicated only partial overlap between Wnt and RSpo ligand activities, suggesting that there may be independent receptor/signaling pathways for RSpo proteins that intersect those of Wnt at the level of β-catenin. Here we summarize the current reported data on the RSpo family and discuss these results in terms of alternate mechanisms of action. We have extended our observations on the potential therapeutic application of RSpo proteins by showing that all 4 human Rspo family members are capable of inducing epithelial proliferation and report the first non-vertebrate RSpo family member.

Although ICAM-3 is implicated in both adhesion and signal transduction events of leukocytes, its low affinity for LFA-1 compared to other ligands of LFA-1 has puzzled many investigators. Here we investigated the role of ICAM-3 in supporting LFA-1-mediated ICAM-1 binding and subsequently cell signaling. We observed that although ICAM-3 binds poorly to LFA-1 expressed on resting T cells, it specifically facilitates and increases LFA-1-mediated adhesion to the high affinity ligand of LFA-1, ICAM-1. We demonstrate that low-affinity binding of LFA-1 to ICAM-3 together with ICAM-1 alters the cell surface distribution of LFA-1 dramatically, inducing large clusters of LFA-1 that facilitate ICAM-1 binding after LFA-1 activation. We found that LFA-1-mediated ICAM-1 cell-cell interactions such as T cell proliferation greatly depend on low affinity LFA-1/ICAM-3 interactions that enhance stable LFA-1/ICAM-1 cell-cell contact. Taken together, these data demonstrate that low affinity LFA-1 binding to ICAM-3 regulates strong LFA-1/ICAM-1-mediated adhesion by driving LFA-1 into clusters to facilitate cell-cell interactions that take place in the immune system.