Fibroblast growth factor 23, klotho and heparin.

PURPOSE OF REVIEW: Fibroblast growth factor (FGF) 23 is a bone-derived hormone that regulates phosphate and vitamin D metabolism by targeting the kidney. When highly elevated, such as in chronic kidney disease (CKD), FGF23 can also target the heart and induce pathologic remodeling. Here we discuss the mechanisms that underlie the physiologic and pathologic actions of FGF23, with focus on its FGF receptors (FGFR) and co-receptors. RECENT FINDINGS: Klotho is a transmembrane protein that acts as an FGFR co-receptor for FGF23 on physiologic target cells. Klotho also exists as a circulating variant, and recent studies suggested that soluble klotho (sKL) can mediate FGF23 effects in cells that do not express klotho. Furthermore, it has been assumed that the actions of FGF23 do not require heparan sulfate (HS), a proteoglycan that acts as a co-receptor for other FGF isoforms. However, recent studies revealed that HS can be part of the FGF23:FGFR signaling complex and modulate FGF23-induced effects. SUMMARY: sKL and HS have appeared as circulating FGFR co-receptors that modulate the actions of FGF23. Experimental studies suggest that sKL protects from and HS accelerates CKD-associated heart injury. However, the in vivo relevance of these findings is still speculative.

Desmoglein-2 harnesses a PDZ-GEF2/Rap1 signaling axis to control cell spreading and focal adhesions independent of cell-cell adhesion.

Desmosomes have a central role in mediating extracellular adhesion between cells, but they also coordinate other biological processes such as proliferation, differentiation, apoptosis and migration. In particular, several lines of evidence have implicated desmosomal proteins in regulating the actin cytoskeleton and attachment to the extracellular matrix, indicating signaling crosstalk between cell-cell junctions and cell-matrix adhesions. In our study, we found that cells lacking the desmosomal cadherin Desmoglein-2 (Dsg2) displayed a significant increase in spreading area on both fibronectin and collagen, compared to control A431 cells. Intriguingly, this effect was observed in single spreading cells, indicating that Dsg2 can exert its effects on cell spreading independent of cell-cell adhesion. We hypothesized that Dsg2 may mediate cell-matrix adhesion via control of Rap1 GTPase, which is well known as a central regulator of cell spreading dynamics. We show that Rap1 activity is elevated in Dsg2 knockout cells, and that Dsg2 harnesses Rap1 and downstream TGFß signaling to influence both cell spreading and focal adhesion protein phosphorylation. Further analysis implicated the Rap GEF PDZ-GEF2 in mediating Dsg2-dependent cell spreading. These data have identified a novel role for Dsg2 in controlling cell spreading, providing insight into the mechanisms via which cadherins exert non-canonical junction-independent effects.