A remarkable range of biological functions and mechanisms of action have been proposed for the protein Klotho. Klotho is a membrane protein with a large extracellular domain. However, its cytoplasmic domain includes just 11 amino acids, which are thought to be unlikely to mediate its regulatory functions. Lack of Klotho causes shortened life span in mice (but so might lots of deleterious mutations), and overexpression of the protein has been reported to extend life span. This was thought to reflect effects on signaling by insulin and insulin-like growth factor 1. Others have proposed that beta-glucuronidase activity of Klotho modifies the transient receptor potential ion channel 5 (TRPV5), supporting localization and activity of the latter at the plasma membrane. Klotho-deficient mice also share characteristics with mice lacking the fibroblast growth factor 23 (FGF23), such as infertility and decreased bone density; indeed, another proposed action of Klotho is the control of mineral metabolism. FGF23 also regulates mineral metabolism, and the latest action proposed for Klotho is to coordinate with the FGF receptor subtype IIIc [FGFR1 (IIIc)] to create a form of the FGFR that mediates binding of FGF23. Klotho turned up in a screen for molecules that bound in vitro to FGF23. FGF23 is itself unusual in that it functions like a hormone; that is, it is produced in bone but is carried in the circulation to regulate kidney function. Transfection of cells that also expressed FGFR1 (IIIc) with Klotho conferred specific high-affinity binding of FGF23 and allowed activation of associated signaling events. In vitro binding assays showed interaction of the extracellular domains of Klotho with a fusion protein of FGF23 with immunoglobulin Fc region. Injection of mice with a monoclonal antibody to Klotho caused changes reminiscent of those in Klotho knockout animals. Circulating FGF23 appears to act selectively at certain tissues, particularly the kidney, even though most tissues have FGFRs. The authors propose that the presence of Klotho may be the key factor that converts FGFR1(IIIc) to a receptor for FGF23, but they don’t propose a grander scheme to account for the range of reported actions of this intriguing protein.
I. Urakawa, Y. Yamazaki, T. Shimada, K. Iijima, H. Hasegawa, K. Okawa, T. Fujita, S. Fukumoto, T. Yamashita, Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770-774 (2006). [PubMed]