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Beta-Pix-dynamin 2 complex promotes colorectal cancer progression by facilitating membrane dynamics
- Source :
- Cellular Oncology (Dordrecht)
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
Abstract
- Purpose Spatiotemporal regulation of cell membrane dynamics is a major process that promotes cancer cell invasion by acting as a driving force for cell migration. Beta-Pix (βPix), a guanine nucleotide exchange factor for Rac1, has been reported to be involved in actin-mediated cellular processes, such as cell migration, by interacting with various proteins. As yet, however, the molecular mechanisms underlying βPix-mediated cancer cell invasion remain unclear. Methods The clinical significance of βPix was analyzed in patients with colorectal cancer (CRC) using public clinical databases. Pull-down and immunoprecipitation assays were employed to identify novel binding partners for βPix. Additionally, various cell biological assays including immunocytochemistry and time-lapse video microscopy were performed to assess the effects of βPix on CRC progression. A βPix-SH3 antibody delivery system was used to determine the effects of the βPix-Dyn2 complex in CRC cells. Results We found that the Src homology 3 (SH3) domain of βPix interacts with the proline-rich domain of Dynamin 2 (Dyn2), a large GTPase. The βPix-Dyn2 interaction promoted lamellipodia formation, along with plasma membrane localization of membrane-type 1 matrix metalloproteinase (MT1-MMP). Furthermore, we found that Src kinase-mediated phosphorylation of the tyrosine residue at position 442 of βPix enhanced βPix-Dyn2 complex formation. Disruption of the βPix-Dyn2 complex by βPix-SH3 antibodies targeting intracellular βPix inhibited CRC cell invasion. Conclusions Our data indicate that spatiotemporal regulation of the Src-βPix-Dyn2 axis is crucial for CRC cell invasion by promoting membrane dynamics and MT1-MMP recruitment into the leading edge. The development of inhibitors that disrupt the βPix-Dyn2 complex may be a useful therapeutic strategy for CRC.
- Subjects :
- rac1 GTP-Binding Protein
Cancer Research
Cytoskeleton rearrangement
Cell
Metal Nanoparticles
RAC1
Video microscopy
Metastasis
src Homology Domains
Cell membrane
Dynamin II
Cell Movement
Cell Line, Tumor
Matrix Metalloproteinase 14
medicine
Humans
Neoplasm Invasiveness
Amino Acid Sequence
Pseudopodia
RNA, Messenger
Phosphorylation
Phosphotyrosine
Dynamin
Chemistry
Cell Membrane
Dynamin 2
Cell migration
General Medicine
Colorectal cancer
Up-Regulation
Cell biology
Gene Expression Regulation, Neoplastic
HEK293 Cells
medicine.anatomical_structure
Oncology
Disease Progression
Molecular Medicine
Original Article
Beta-Pix
Src kinase
Gold
Guanine nucleotide exchange factor
Colorectal Neoplasms
Rho Guanine Nucleotide Exchange Factors
Protein Binding
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- ISSN :
- 22113436 and 22113428
- Volume :
- 44
- Database :
- OpenAIRE
- Journal :
- Cellular Oncology
- Accession number :
- edsair.doi.dedup.....f2b35b1e937b4e45940d95bf11e1370c
- Full Text :
- https://doi.org/10.1007/s13402-021-00637-6