Abstract
Platelet-derived growth factor (PDGF) has mitogenic and chemotactic effects on fibroblasts. An increase in intracellular Ca2+ is one of the first events that occurs following the stimulation of PDGF receptors (PDGFRs). PDGF activates Ca2+ elevation by activating the phospholipase C gamma (PLCγ)-signaling pathway, resulting in ER Ca2+ release. Store-operated Ca2+ entry (SOCE) is the major form of extracellular Ca2+ influx following depletion of ER Ca2+ stores and stromal interaction molecule 1 (STIM1) is a key molecule in the regulation of SOCE. In this study, wild-type and STIM1 knockout mouse embryonic fibroblasts (MEF) cells were used to investigate the role of STIM1 in PDGF-induced Ca2+ oscillation and its functions in MEF cells. The unexpected findings suggest that STIM1 knockout enhances PDGFR–PLCγ–STIM2 signaling, which in turn increases PDGF-BB-induced Ca2+ elevation. Enhanced expressions of PDGFRs and PLCγ in STIM1 knockout cells induce Ca2+ release from the ER store through PLCγ–IP3 signaling. Moreover, STIM2 replaces STIM1 to act as the major ER Ca2+ sensor in activating SOCE. However, activation of PDGFRs also activate Akt, ERK, and JNK to regulate cellular functions, such as cell migration. These results suggest that alternative switchable pathways can be observed in cells, which act downstream of the growth factors that regulate Ca2+ signaling.
Highlights
Ca2+ plays an important and ubiquitous role in intracellular signaling in response to several cellular functions, including cell proliferation, development, differentiation, migration, transcription factor activation, and apoptosis [1,2]
Quantification analysis revealed that the endoplasmic reticulum (ER) released Ca2+ was similar in both cell types (Figure 1B), but Store-operated Ca2+ entry (SOCE) was significantly reduced in mouse embryonic fibroblasts (MEF)-stromal interaction molecule 1 (STIM1)−/− cells compared to that in MEF-WT cells (Figure 1C)
These results suggest that TG-mediated Ca2+ elevation after extracellular 2 mM Ca2+ exposure showed an initial peak (Figure 1E) and that the total Ca2+ elevation (Figure 1F) in MEF-WT cells was more dominant than that in MEF-STIM1−/− cells
Summary
Ca2+ plays an important and ubiquitous role in intracellular signaling in response to several cellular functions, including cell proliferation, development, differentiation, migration, transcription factor activation, and apoptosis [1,2]. To coordinate these functions, Ca2+ signaling is regulated meticulously and is distinguished by several patterns of spatio–temporal parameters with altering amplitude, frequency, or duration [2,3,4]. After the ligand binds to receptor tyrosine kinase (RTK), phospholipase C gamma (PLCγ) is phosphorylated and activated, which in turn hydrolyzes membrane-bound phosphatidylinositol 4,5-bisphosphate (PIP2) into 1,4,5-inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 can induce the diffusion of Ca2+ from the ER into the cytoplasm through the IP3 receptor (IP3R) on the ER membrane
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