Journal
JOURNAL OF CELL SCIENCE
Volume 133, Issue 20, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.248823
Keywords
Mechanical signaling; Mechanotransduction; Integrin; TRPV4; CD98hc
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Funding
- National Institutes of Health [R01-EB020004, R01-HL146134, R01-HL141853, R01-HL130845, R01-HL093242]
- UEHARA Memorial Foundation
- Japan Society for the Promotion of Science (JSPS)
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One of the most rapid (less than 4 ms) transmembrane cellular mechanotransduction events involves activation of transient receptor potential vanilloid 4 (TRPV4) ion channels by mechanical forces transmitted across cell surface beta 1 integrin receptors on endothelial cells, and the transmembrane solute carrier family 3 member 2 (herein denoted CD98hc, also known as SLC3A2) protein has been implicated in this response. Here, we show that beta 1 integrin, CD98hc and TRPV4 all tightly associate and colocalize in focal adhesions where mechanochemical conversion takes place. CD98hc knockdown inhibits TRPV4-mediated calcium influx induced by mechanical forces, but not by chemical activators, thus confirming themechanospecificity of this signaling response. Molecular analysis reveals that forces applied to beta 1 integrin must be transmitted from its cytoplasmic C terminus via the CD98hc cytoplasmic tail to the ankyrin repeat domain of TRPV4 in order to produce ultrarapid, force-induced channel activation within the focal adhesion.
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