Ca2+ influx has been postulated to modulate the signaling pathway of transforming growth factor-β (TGF-β); however, the underlying mechanism and functional significance of TGF-β-induced stimulation of Ca2+ influx are unclear. We show here that TGF-β 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-β enhances plasma membrane localization of IP3RIII, whereas the sarcoplasmicendoplasmic reticulum Ca2+-ATPase (SERCA) preferentially translocates to the nucleus. Untreated mesangial cells exhibit actin filamentous protrusions on the cell surface, and treatment with TGF-β dramatically reduces this pattern. The alterations in the actin cytoskeleton by TGF-β are dependent on TGF-β-induced Ca2+ influx. These studies identify a novel pathway by which TGF-β regulates Ca2+ influx and induces cytoskeletal alterations.
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