PRAM-1 is required for optimal integrin-dependent neutrophil function.
PML-retinoic acid receptor alpha (RARalpha) regulated adaptor molecule 1 (PRAM-1) is an intracellular adaptor molecule that is upregulated during the induced granulocytic differentiation of promyelocytic leukemic cells and during normal human myelopoiesis. This report describes the generation of PRAM-1-deficient mice and an analysis of the function of this adaptor in neutrophil differentiation and mature neutrophil function. We demonstrate here that neutrophil differentiation is not impaired in PRAM-1-deficient mice and that PRAM-1-deficient neutrophils function normally following engagement of Fcgamma receptors. In contrast, mature PRAM-1-null neutrophils exhibit significant defects in adhesion-dependent reactive oxygen intermediate production and degranulation. Surprisingly, other integrin-dependent responses, such as cell spreading and activation of several signaling pathways, are normal. Together, these findings demonstrate the uncoupling of key integrin-dependent responses in the absence of PRAM-1 and show this adaptor to be critical for select integrin functions in neutrophils.
Clemens
Regina A
RA
Dept. of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA.
Newbrough
Sally A
SA
Chung
Elaine Y
EY
Gheith
Shereen
S
Singer
Andrew L
AL
Koretzky
Gary A
GA
Peterson
Erik J
EJ
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation; D015870:Gene Expression; D018390:Gene Targeting; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D009895:Opsonin Proteins; D010587:Phagocytosis; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016897:Respiratory Burst / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D013211:Staphylococcus aureus
D048868:Adaptor Proteins, Signal Transducing; D016023:Integrins; D009895:Opsonin Proteins; C430907:PRAM1 protein, human; D011506:Proteins; D002118:Calcium