The primary mediator of Ca2+-dependent signaling in eukaryotic cells is calmodulin, which serves as a high affinity intracellular Ca2+ receptor. Calmodulin is a ubiquitous, highly conserved protein that plays a critical role in numerous essential cellular functions, including Ca2+ transport, cell motility, cytoskeletal assembly, protein phosphorylation/dephosphorylation, cell proliferation and cell cycle progression.
The effects of calmodulin are produced by direct interaction with target enzymes or indirectly via multiple specific kinases. The crystal structure of Ca2+-bound calmodulin has been solved both in the absence and presence of associated peptides. As the concentration of intracellular free Ca2+ transiently rises, calmodulin undergoes a conformational change that allows it to bind to calmodulin-binding domains on a variety of proteins. Calmodulin-binding proteins typically contain either basic amphiphilic a-helices or IQ motifs. IQ motifs consist of approximately 25 residues with the core consensus sequence IQXXXRGXXXR, (where X is any amino acid). Ca2+-free (apo-) calmodulin can also bind IQ motifs.
Because calmodulin is essential in normal cellular proliferation, abnormal cellular proliferation should exhibit alterations in levels of calmodulin, and/or its interactions with target proteins. The calmodulin content in several transformed cells in culture and tumor tissue is significantly increased. For example, chicken embryo fibroblasts transformed by Rous sarcoma virus and a human acute lymphoblastic leukemia cell lines have two- to three-fold higher calmodulin levels than normal cells. Moreover, we and others have demonstrated that transformed cells have altered levels of selected calmodulin-binding proteins. Importantly, calmodulin was identified using DNA microarray technology to be upregulated in highly metastatic melanoma cells.