Calmodulin is the principal calcium sensor of the eukaryotic cell. When intracellular calcium level is low, calmodulin is inactive and bound to particular substrates denominated calmodulin binding proteins. An increase of intracellular calcium activates calmodulin and the calcium-rich form of calmodulin regulates the activity of a large array of enzymes that are part of the intracellular signaling cascades controlling cellular homeostasis.

Some proteins bind the inactive form of calmodulin and regulate its accessibility to its substrates. High levels of cytosolic calcium and phosphorylation of the calmodulin- binding domain impair the interactions between calpacitins and calmodulin.

EDF-1, an endothelial differentiation suppressor molecule, is a novel member of the calmodulin-binding protein family, which includes neuronal RC3, GAP43 and PEP-19. EDF-1 is not tissue specific, while RC3, GAP43 and PEP-19 are expressed only in the central nervous system.

Analogously to other calmodulin-binding proteins, an increase of cytosolic calcium reduces the binding of EDF-1 to calmodulin and facilitates the phosphorylation of calmodulin binding domain by PKC. This phosphorylation prevents the interaction between EDF-1 and calmodulin so that the free calmodulin can be readily activated (high calcium) or bind others molecules (low calcium).

On the other hand, phosphorylated EDF-1 accumulates into the nucleus, where EDF-1 acts as a bridge between the TATA Binding Protein (TBP) and various transcription factors, thus behaving as a trascriptional coactivator. It is intriguing to consider the double role of EDF-1: in the cytosol EDF-1 regulates calmodulin function acting as a calmodulin-binding protein, whereas in the nucleus EDF-1 functions as transcriptional coactivator.