Document Detail

Homeostatic intracellular-free Ca2+ is permissive for Rap1-mediated constitutive activation of alpha4 integrins on eosinophils.
MedLine Citation:
PMID:  18390735     Owner:  NLM     Status:  MEDLINE    
Although much progress has been made in understanding the molecular mechanisms underlying agonist-induced "inside-out" activation of integrins, little is known about how basal levels of integrin function are maintained. This is particularly important for nonactivated eosinophils, where intermediate activation of alpha(4)beta(1) integrin supports recruitment to endothelial cells under flow conditions. Depletion of intracellular Ca(2+) and pharmacological inhibition of phospholipase C (but not other intracellular signaling molecules, including PI3K, ERK1/2, p38 MAPK, and tyrosine kinase activity) abrogated basal alpha(4) integrin activity in nonactivated eosinophils. Basal alpha(4) integrin activation was associated with activation of the small GTPase Rap1, a known regulator of agonist-induced integrin function. Basal Rap activation was dependent upon phospholipase C, but not intracellular Ca(2+). However, depletion of intracellular Ca(2+) in CD34(+) hematopoietic progenitor cells abolished RapV12-mediated induction of alpha(4) integrin activity. Thus, residual Rap activity or constitutively active Rap activity in Ca(2+)-depleted cells is not sufficient to induce alpha(4) integrin activation. These data suggest that activation of functional alpha(4) integrin activity in resting eosinophils is mediated by Rap1 provided that the intracellular-free Ca(2+) is at a normal homeostatic concentration.
Laurien H Ulfman; Vera M Kamp; Corneli W van Aalst; Liesbeth P Verhagen; Marjolein E Sanders; Kris A Reedquist; Miranda Buitenhuis; Leo Koenderman
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  180     ISSN:  0022-1767     ISO Abbreviation:  J. Immunol.     Publication Date:  2008 Apr 
Date Detail:
Created Date:  2008-04-08     Completed Date:  2008-07-01     Revised Date:  2009-03-23    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5512-9     Citation Subset:  AIM; IM    
Department of Respiratory Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
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MeSH Terms
Calcium / metabolism*
Eosinophils / immunology,  metabolism*
Integrin alpha4 / immunology,  metabolism*
Type C Phospholipases / metabolism
Vascular Cell Adhesion Molecule-1 / metabolism
rap1 GTP-Binding Proteins / metabolism*
Reg. No./Substance:
0/Vascular Cell Adhesion Molecule-1; 143198-26-9/Integrin alpha4; 7440-70-2/Calcium; EC 3.1.4.-/Type C Phospholipases; EC GTP-Binding Proteins

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