Tetraspanin-enriched microdomains regulate digitation junctions

Abstract

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.

Targeting CD82/KAI1 for Precision Therapeutics in Surmounting Metastatic Potential in Breast Cancer

“…For instance, CD82 is known to diminish lamellipodia formation and perturb actin organization by the deregulation of Rac1, RhoA, and their effectors cofilin and Rho kinase. Tetraspanins have also been reported to control various cell functions such as cell adhesion, migration and communication via the regulation of digitation junctions [34]. CD82 has been observed to inhibit cell movement by hampering the formation and development of both cellular protrusions and retractions at the cellular level [31].…”

Differential tetraspanin genes expression and subcellular localization during mutualistic interactions in Phaseolus vulgaris

“…Given their wide distribution in mammals, insects, fungi, mosses, and plants, tetraspanins likely coemerged in multicellular organisms during evolution [18]. In animal cells, tetraspanins are typically localized at the cell–cell interface in tetraspanin-enriched microdomains (TEMs), where they associate with each other and with other membrane-bound molecules and build important molecular platforms or cell–cell interactions [19, 20]. Tetraspanins get their name from their four transmembrane domains.…”

Identification of the Tetraspanin CD9 as an Interaction Partner of Organic Cation Transporters 1 and 2

“…18 The hOCTs are highly expressed in epithelial cells: The co-localization of CD9 and hOCT2 in membrane protrusion of MDCK cells suggests that they are co-expressed in digital junctions, which may represent a transitional contact mechanism between epithelial cells before adherens junctions appear and reinforce the cell-cell contacts. 41 The CD9-hOCT2 interaction also can probably take place in vivo in renal tissue, since we observed an expression of mRNA for CD9 in a preparation of human renal proximal tubules (Suppl. Fig.…”