Tetraspanin-enriched microdomains regulate digitation junctions
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Tetraspanins co-emerged with multi-cellular organisms during evolution are typically localized at the cell–cell interface, and form tetraspanin-enriched microdomains (TEMs) by associating with each other and other membrane molecules. Tetraspanins affect various biological functions, but how tetraspanins engage in multi-faceted functions at the cellular level is largely unknown. When cells interact, the membrane microextrusions at the cell–cell interfaces form dynamic, digit-like structures between cells, which we term digitation junctions (DJs). We found that (1) tetraspanins CD9, CD81, and CD82 and (2) TEM-associated molecules integrin α3β1, CD44, EWI2/PGRL, and PI-4P are present in DJs of epithelial, endothelial, and cancer cells. Tetraspanins and their associated molecules also regulate the formation and development of DJs. Moreover, (1) actin cytoskeleton, RhoA, and actomyosin activities and (2) growth factor receptor-Src-MAP kinase signaling, but not PI-3 kinase, regulate DJs. Finally, we showed that DJs consist of various forms in different cells. Thus, DJs are common, interactive structures between cells, and likely affect cell adhesion, migration, and communication. TEMs probably modulate various cell functions through DJs. Our findings highlight that DJ morphogenesis reflects the transition between cell–matrix adhesion and cell–cell adhesion and involves both cell–cell and cell–matrix adhesion molecules.
KeywordsCell–cell adhesion Cell–cell communication Microextrusion Nanotubule Tetraspanin Integrin
Dulbecco’s modified eagle medium
Fetal calf serum
Global microarray meta-analysis
Gene expression omnibus
Hepatocyte growth factor
Human microvascular endothelial cell
Methyl beta cyclodextrin
Membrane tubular structures
Myosin light chain kinase
Total internal reflection fluorescence
This work was supported by National Institutes of Health Research Grants CA096991, HL132553, and HL137819, American Heart Association Grant-in-Aid 13GRNT17040028, Oklahoma Center for Advanced Science and Technology Grant, and Chapman Foundation (to X. A. Z.). We thank Ms. Kathy Kyler for English editing.
Conceived and designed the experiments: XAZ. Performed the experiments: CH, CF, XW, JDW, FZ, YHZ, SAC, and XAZ. Analyzed the data: CH, JDW, and XAZ. Contributed reagents/materials/analysis tools: TC. Wrote the paper: XAZ.
Compliance with ethical standards
Conflict of interest
The authors declare no competing financial interests.