Dataset Information

STIM1 Knockout Enhances PDGF-Mediated Ca²⁺ Signaling through Upregulation of the PDGFR?PLC??STIM2 Cascade.

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 (PLC?)-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?PLC?–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.

SUBMITTER: Huang TY

PROVIDER: S-EPMC6032054 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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STIM1 Knockout Enhances PDGF-Mediated Ca2+ Signaling through Upregulation of the PDGFR⁻PLCγ⁻STIM2 Cascade.

Huang Tzu-Yu TY Lin Yi-Hsin YH Chang Heng-Ai HA Yeh Tzu-Ying TY Chang Ya-Han YH Chen Yi-Fan YF Chen Ying-Chi YC Li Chun-Chun CC Chiu Wen-Tai WT

International journal of molecular sciences 20180618 6

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 ...[more]

PMID: 29912163

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Project description:STIM1 is an endoplasmic reticulum protein with a role in Ca2+ mobilization and signaling. As a sensor of intraluminal Ca2+ levels, STIM1 modulates plasma membrane Ca2+ channels to regulate Ca2+ entry. In neuroblastoma SH-SY5Y cells and in familial Alzheimer's disease patient skin fibroblasts, STIM1 is cleaved at the transmembrane domain by the presenilin-1-associated γ-secretase, leading to dysregulation of Ca2+ homeostasis. In this report, we investigated expression levels of STIM1 in brain tissues (medium frontal gyrus) of pathologically confirmed Alzheimer's disease patients, and observed that STIM1 protein expression level decreased with the progression of neurodegeneration. To study the role of STIM1 in neurodegeneration, a strategy was designed to knock-out the expression of STIM1 gene in the SH-SY5Y neuroblastoma cell line by CRISPR/Cas9-mediated genome editing, as an in vitro model to examine the phenotype of STIM1-deficient neuronal cells. It was proved that, while STIM1 is not required for the differentiation of SH-SY5Y cells, it is absolutely essential for cell survival in differentiating cells. Differentiated STIM1-KO cells showed a significant decrease of mitochondrial respiratory chain complex I activity, mitochondrial inner membrane depolarization, reduced mitochondrial free Ca2+ concentration, and higher levels of senescence as compared with wild-type cells. In parallel, STIM1-KO cells showed a potentiated Ca2+ entry in response to depolarization, which was sensitive to nifedipine, pointing to L-type voltage-operated Ca2+ channels as mediators of the upregulated Ca2+ entry. The stable knocking-down of CACNA1C transcripts restored mitochondrial function, increased mitochondrial Ca2+ levels, and dropped senescence to basal levels, demonstrating the essential role of the upregulation of voltage-operated Ca2+ entry through Cav1.2 channels in STIM1-deficient SH-SY5Y cell death.Key messagesSTIM1 protein expression decreases with the progression of neurodegeneration in Alzheimer's disease. STIM1 is essential for cell viability in differentiated SH-SY5Y cells. STIM1 deficiency triggers voltage-regulated Ca2+ entry-dependent cell death. Mitochondrial dysfunction and senescence are features of STIM1-deficient differentiated cells.

Dataset Information

STIM1 Knockout Enhances PDGF-Mediated Ca²⁺ Signaling through Upregulation of the PDGFR?PLC??STIM2 Cascade.

Publications

STIM1 Knockout Enhances PDGF-Mediated Ca<sup>2+</sup> Signaling through Upregulation of the PDGFR⁻PLCγ⁻STIM2 Cascade.

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Dataset Information

STIM1 Knockout Enhances PDGF-Mediated Ca2+ Signaling through Upregulation of the PDGFR?PLC??STIM2 Cascade.

Publications

STIM1 Knockout Enhances PDGF-Mediated Ca<sup>2+</sup> Signaling through Upregulation of the PDGFR⁻PLCγ⁻STIM2 Cascade.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

STIM1 Knockout Enhances PDGF-Mediated Ca²⁺ Signaling through Upregulation of the PDGFR?PLC??STIM2 Cascade.