Abstract
Calmodulin (CaM) is the principal Ca2+ sensor protein in all eukaryotic cells, that upon binding to target proteins transduces signals encoded by global or subcellular-specific changes of Ca2+ concentration within the cell. The Ca2+/CaM complex as well as Ca2+-free CaM modulate the activity of a vast number of enzymes, channels, signaling, adaptor and structural proteins, and hence the functionality of implicated signaling pathways, which control multiple cellular functions. A basic and important cellular function controlled by CaM in various ways is cell motility. Here we discuss the role of CaM-dependent systems involved in cell migration, tumor cell invasiveness, and metastasis development. Emphasis is given to phosphorylation/dephosphorylation events catalyzed by myosin light-chain kinase, CaM-dependent kinase-II, as well as other CaM-dependent kinases, and the CaM-dependent phosphatase calcineurin. In addition, the role of the CaM-regulated small GTPases Rac1 and Cdc42 (cell division cycle protein 42) as well as CaM-binding adaptor/scaffold proteins such as Grb7 (growth factor receptor bound protein 7), IQGAP (IQ motif containing GTPase activating protein) and AKAP12 (A kinase anchoring protein 12) will be reviewed. CaM-regulated mechanisms in cancer cells responsible for their greater migratory capacity compared to non-malignant cells, invasion of adjacent normal tissues and their systemic dissemination will be discussed, including closely linked processes such as the epithelial–mesenchymal transition and the activation of metalloproteases. This review covers as well the role of CaM in establishing metastatic foci in distant organs. Finally, the use of CaM antagonists and other blocking techniques to downregulate CaM-dependent systems aimed at preventing cancer cell invasiveness and metastasis development will be outlined.
Highlights
Calcium is a widespread second messenger that controls a variety of mechanisms required for cell motility
This apparent contradiction was dispelled by the discovery that synergistic opening of the mechanosensitive Ca2+ channel TRPM7 and endoplasmic reticulum-located IP3R, generate small Ca2+ flickers which are short in duration, predominantly occurring at the advancing front edge of the cell, which activate the Ca2+-dependent systems, including calmodulin (CaM) and CaM-dependent systems, required for cell migration [3]
To understand the anomalous behavior of tumor cells in this respect, we summarize in this article basic mechanisms involved in the migration of non-tumor cells, in order to provide a general view of the molecular mechanisms implicated
Summary
Calcium is a widespread second messenger that controls a variety of mechanisms required for cell motility. As pointed out by Wei et al [3], this asymmetric Ca2+ distribution appears at first sight paradoxical, as the leading front is where cells accumulate systems necessary for cell migration requiring Ca2+ for their functionality, such as those controlling cytoskeleton remodeling or the assembly and dynamics of focal adhesions This apparent contradiction was dispelled by the discovery that synergistic opening of the mechanosensitive Ca2+ channel TRPM7 (transient receptor potential melastatin channel 7) and endoplasmic reticulum-located IP3R (inositol 3-phosphate receptor), generate small Ca2+ flickers which are short in duration (ranging from 10 ms to 2 s), predominantly occurring at the advancing front edge of the cell, which activate the Ca2+-dependent systems, including calmodulin (CaM) and CaM-dependent systems, required for cell migration [3] (reviewed in [4]). The four EF-hand-containing Ca2+-receptor protein CaM has been shown to be a major ruler in all eukaryote cells upon binding to target proteins
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