TGF-β-induced Ca2+ influx involves the type IIIIP3 receptor and regulates actin cytoskeleton

Ca2+ influx has been postulated to modulate the signaling pathway of transforming growth factor-beta (TGF-beta); however, the underlying mechanism and functional significance of TGF-beta-induced stimulation of Ca2+ influx are unclear. We show here that TGF-beta stimulates Ca2+ influx in mesangial cells without Ca2+ release. The influx of Ca2+ is prevented by pharmacological inhibitors of inositol 1,4,5-trisphosphate receptors (IP3R) as well as specific antibodies to type III IP3R (IP3RIII) but not to type I IP3R (IP3RI). TGF-beta enhances plasma membrane localization of IP3RIII, whereas the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) preferentially translocates to the nucleus. Untreated mesangial cells exhibit actin filamentous protrusions on the cell surface, and treatment with TGF-beta dramatically reduces this pattern. The alterations in the actin cytoskeleton by TGF-beta are dependent on TGF-beta-induced Ca2+ influx. These studies identify a novel pathway by which TGF-beta regulates Ca2+ influx and induces cytoskeletal alterations.