Thrombospondin is a matrix glycoprotein found in various cells that can modulate cell attachment, migration, and proliferation. We now show that intact soluble thrombospondin causes a transient [Ca] increase in IMR-90 fibroblasts. This [Ca] increase is mediated partly by the RGD-containing domain of thrombospondin that binds to the integrin v3 as demonstrated by inhibitor studies using anti-v3 antibody and RGD-containing peptides. A non-RGD and non-v3 component of this [Ca] increase is mediated by the carboxyl-terminal domain of thrombospondin through an unidentified receptor on fibroblasts as shown by the antibody to the carboxyl-terminal of thrombospondin, C6.7. In addition, the carboxyl-terminal derived peptide, RFYVVMWK, also triggers [Ca] increase in 35% of fibroblasts. Both EGTA and Ni block the entire [Ca] increase indicating that this is due to an influx of extracellular Ca. B6H12, an antibody to the integrin-associated protein, blocks this [Ca]increase by 50%, suggesting that some of the Ca might be entering through an integrin-associated calcium channel. The current findings demonstrate that multiple domains on thrombospondin can trigger signal transduction events by increasing [Ca] through their interactions with different cell receptors.

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