Beta2 integrins target Rap GTPases to the plasma membrane by means of degranulation.
We report the novel observation that engagement of beta2 integrins on human neutrophils is accompanied by increased levels of the small GTPases Rap1 and Rap2 in a membrane-enriched fraction and a concomitant decrease of these proteins in a granule-enriched fraction. In parallel, we observed a similar time-dependent decrease of gelatinase B (a marker of specific and gelatinase B-containing granules) but not myeloperoxidase (a marker of azurophil granules) in the granule fraction, and release of lactoferrin (a marker of specific granules) in the extracellular medium. Furthermore, inhibition of Src tyrosine kinases, or phosphoinositide 3-kinase with PP1 or LY294002, respectively, blocked beta2 integrin-induced degranulation and the redistribution of Rap1 and Rap2 to a membrane-enriched fraction. Consequently, the beta2 integrin-dependent exocytosis of specific and gelatinase B-containing granules occurs via a Src tyrosine kinase/phosphoinositide 3-kinase signaling pathway and is responsible for the translocation of Rap1 and Rap2 to the plasma membrane in human neutrophils.
Dib
Karim
K
Centre for Cancer Research and Cell Biology, Division of Infection and Immunity, Queen's University of Belfast, Whitla Medical Building, Second Floor, 97 Lisburn Road, Belfast, Northern Ireland BT9 7BL, UK. k.dib@qub.ac.uk
Axelsson
Lena
L
Andersson
Tommy
T
D018821:CD18 Antigens / Q000378:metabolism*; D015550:Cell Degranulation; D002462:Cell Membrane / Q000201:enzymology*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009504:Neutrophils / Q000201:enzymology / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020668:rap GTP-Binding Proteins / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D018821:CD18 Antigens; D002867:Chromones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C430803:RAP1A protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019061:src-Family Kinases; C116756:RAP2A protein, human; D020668:rap GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins