PUBLICATION
RAC1-Dependent ORAI1 Translocation to the Leading Edge Supports Lamellipodia Formation and Directional Persistence
- Authors
- Lopez-Guerrero, A.M., Espinosa-Bermejo, N., Sanchez-Lopez, I., Macartney, T., Pascual-Caro, C., Orantos-Aguilera, Y., Rodriguez-Ruiz, L., Perez-Oliva, A.B., Mulero, V., Pozo-Guisado, E., Martin-Romero, F.J.
- ID
- ZDB-PUB-200422-171
- Date
- 2020
- Source
- Scientific Reports 10: 6580 (Journal)
- Registered Authors
- Mulero, Victor
- Keywords
- none
- MeSH Terms
-
- Actin Cytoskeleton/genetics
- rac1 GTP-Binding Protein/genetics*
- Neoplasm Invasiveness/genetics
- Neoplasm Invasiveness/pathology
- Cell Line, Tumor
- Adaptor Proteins, Signal Transducing/genetics
- Cell Membrane/metabolism
- Cortactin/genetics*
- Cell Movement/genetics
- Actin-Related Protein 2-3 Complex/genetics
- ORAI1 Protein/genetics*
- Osteosarcoma/genetics*
- Osteosarcoma/metabolism
- Osteosarcoma/pathology
- Humans
- Pseudopodia/genetics*
- Pseudopodia/metabolism
- Animals
- PubMed
- 32313105 Full text @ Sci. Rep.
Citation
Lopez-Guerrero, A.M., Espinosa-Bermejo, N., Sanchez-Lopez, I., Macartney, T., Pascual-Caro, C., Orantos-Aguilera, Y., Rodriguez-Ruiz, L., Perez-Oliva, A.B., Mulero, V., Pozo-Guisado, E., Martin-Romero, F.J. (2020) RAC1-Dependent ORAI1 Translocation to the Leading Edge Supports Lamellipodia Formation and Directional Persistence. Scientific Reports. 10:6580.
Abstract
Tumor invasion requires efficient cell migration, which is achieved by the generation of persistent and polarized lamellipodia. The generation of lamellipodia is supported by actin dynamics at the leading edge where a complex of proteins known as the WAVE regulatory complex (WRC) promotes the required assembly of actin filaments to push the front of the cell ahead. By using an U2OS osteosarcoma cell line with high metastatic potential, proven by a xenotransplant in zebrafish larvae, we have studied the role of the plasma membrane Ca2+ channel ORAI1 in this process. We have found that epidermal growth factor (EGF) triggered an enrichment of ORAI1 at the leading edge, where colocalized with cortactin (CTTN) and other members of the WRC, such as CYFIP1 and ARP2/3. ORAI1-CTTN co-precipitation was sensitive to the inhibition of the small GTPase RAC1, an upstream activator of the WRC. RAC1 potentiated ORAI1 translocation to the leading edge, increasing the availability of surface ORAI1 and increasing the plasma membrane ruffling. The role of ORAI1 at the leading edge was studied in genetically engineered U2OS cells lacking ORAI1 expression that helped us to prove the key role of this Ca2+ channel on lamellipodia formation, lamellipodial persistence, and cell directness, which are required for tumor cell invasiveness in vivo.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping