RT Journal Article
T1 Critical Signaling Events in the Mechanoactivation of Human Mast Cells through p.C492Y-ADGRE2
A1 Olivera, Ana
A1 Metcalfe, Dean D.
A1 Kastner, Daniel L.
A1 Boyden, Steven E.
A1 Komarow, Hirsh D.
A1 Tobío Ageitos, Araceli
A1 Smelkinson, Margery G.
A1 Bai, Yun
A1 Bandara, Geethani
A1 Naranjo, Andrea N.
AB A role for the adhesion G-protein coupled receptor ADGRE2 or EMR2 in mechanosensing was revealed by the finding of a missense substitution (p.C492Y) associated with familial vibratory urticaria. In these patients, friction of the skin induces mast cell hyper-degranulation through p.C492Y-ADGRE2, causing localized hives, flushing, and hypotension. We have now characterized the responses and intracellular signals elicited by mechanical activation in human mast cells expressing p.C492Y-ADGRE2 and attached to dermatan sulfate, a ligand for ADGRE2. The presence of p.C492Y-ADGRE2 reduced the threshold to activation and increased the extent of degranulation along with the percentage of  mast cells responding. Vibration caused phospholipase C activation, transient increases in cytosolic calcium, and downstream activation of phosphoinositide 3-kinase and extracellular signaleregulated kinases 1 and 2 by Gbg, Gaq/11, and Gai/o-independent mechanisms. Degranulation induced by vibration was dependent on phospholipase C pathways, including calcium, protein kinase C, and phosphoinositide 3-kinase but not extracellular signaleregulated kinases 1/2 pathways, along with pertussis toxin-sensitive signals. In addition, mechanoactivation of mast cells stimulated the synthesis and release of prostaglandin D2, to our knowledge a previously unreported mediator in vibratory urticaria, and extracellular signaleregulated kinases 1/2 activation was required for this response together with calcium, protein kinase C, and to some extent, phosphoinositide 3-kinase. Our studies thus identified critical molecular events initiated by mechanical forces and potential therapeutic targets for patients with vibratory urticaria.
PB Elsevier
SN 0022-202X
YR 2020
FD 2020
LK http://hdl.handle.net/10347/31927
UL http://hdl.handle.net/10347/31927
LA eng
NO Naranjo, A.N., Bandara, G., Bai, Y., Smelkinson, M.G., Tobío, A. Komarow, H.D., Boyden, S.E., Kastner, D.L., Metcalfe, D.D., Olivera, A. (2020). Critical Signaling Events in the Mechanoactivation of Human Mast Cells through p.C492Y-ADGRE2. Journal of Investigative Dermatology, 140 (11), pp 2210-2220.e5
NO This work was supported by the Division of Intramural Research within the National Institute of Allergy and Infectious Diseases and the National Human Genome Research Institute at the National Institutes of Health.
DS Minerva
RD 22 abr 2026