Abstract
The social amoebozoan Dictyostelium discoideum undergoes a developmental sequence wherein an extracellular matrix (ECM) sheath surrounds a group of differentiating cells. This sheath is comprised of proteins and carbohydrates, like the ECM of mammalian tissues. One of the characterized ECM proteins is the cysteine-rich, EGF-like (EGFL) repeat-containing, calmodulin (CaM)-binding protein (CaMBP) CyrA. The first EGFL repeat of CyrA increases the rate of random cell motility and cyclic AMP-mediated chemotaxis. Processing of full-length CyrA (~63 kDa) releases two major EGFL repeat-containing fragments (~45 kDa and ~40 kDa) in an event that is developmentally regulated. Evidence for an EGFL repeat receptor also exists and downstream intracellular signaling pathways involving CaM, Ras, protein kinase A and vinculin B phosphorylation have been characterized. In total, these results identify CyrA as a true matricellular protein comparable in function to tenascin C and other matricellular proteins from mammalian cells. Insight into the regulation and processing of CyrA has also been revealed. CyrA is the first identified extracellular CaMBP in this eukaryotic microbe. In keeping with this, extracellular CaM (extCaM) has been shown to be present in the ECM sheath where it binds to CyrA and inhibits its cleavage to release the 45 kDa and 40 kDa EGFL repeat-containing fragments. The presence of extCaM and its role in regulating a matricellular protein during morphogenesis extends our understanding of CaM-mediated signal transduction in eukaryotes.
Highlights
Repeat-containing cleavage products activate the EGFR and downstream signaling pathways. Studies on these proteins strongly suggest that a primary function of cysteine-rich, EGFL repeats present within extracellular matrix (ECM) proteins is to regulate cell movement
CyrA is characterized by the presence of a signal sequence, a CaM-binding domain (CaMBD) and four tandem EGFL repeats (EGFL1-4) that comprise the C-terminal region of the protein (Figure 1, A)
The cysteine-rich CyrA is not homologous to any mammalian protein but it does share certain defining characteristics with ECM proteins designated as matricellular proteins
Summary
The matricellular protein component of the extracellular matrix (ECM) functions as a modulator and mediator of cell-matrix interactions [1±3]. EGFL repeats, which can be present as single entities or as multiple tandem repeats, are a widespread but highly variable domain containing cysteine residues reflecting the position of these residues in EGF [7,8] While they have been well studied in certain human proteins they are present in lower eukaryotes, including the model organisms Drosophila melanogaster and Dictyostelium discoideum [9±11]. The EGFL repeats of TSP-1 increase the rate of cell movement by activating intracellular signaling events [15]. When cleaved by matrix metalloproteinase 2 (MMP2), the resulting EGFL repeat-containing cleavage products activate the EGFR and downstream signaling pathways Overall, studies on these proteins strongly suggest that a primary function of cysteine-rich, EGFL repeats present within ECM proteins is to regulate cell movement. The results for Dictyostelium suggest this function may be evolutionarily conserved
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