Integrin alpha(M)beta(2) Clustering Triggers Phosphorylation and Activation of Protein Kinase C delta that Regulates Transcription Factor Foxp1 Expression in Monocytes

Integrins are type I membrane and heterodimeric (alpha beta) cell adhesion receptors. Intracellular signals triggered by ligand-bound integrins are important for cell growth, differentiation, and migration. Integrin alpha(M)beta(2) plays key roles in myeloid cell adhesion, phagocytosis, and degranulation. In this study, we show that protein kinase C (PKC) delta is involved in alpha(M)beta(2) signaling. In human monocytic U937 cells and peripheral blood monocytes, alpha(M)beta(2) clustering induced PKC delta translocation to the plasma membrane, followed by Tyr(311) phosphorylation and activation of PKC delta by the src family kinases Hck and Lyn. Interestingly, alpha(M)beta(2)-induced PKC delta Tyr(311) phosphorylation was not mediated by the tyrosine kinase Syk, which is a well reported kinase in beta(2) integrin signaling. Analysis of the beta(2) cytoplasmic tail showed that the sequence Asn(727)-Ser(734) is important in alpha(M)beta(2)-induced PKC delta Tyr(311) phosphorylation. It has been shown that alpha(M)beta(2) clustering regulates the expression the transcription factor Foxp1 that has a role in monocyte differentiation. We show that Foxp1 expression was reduced in monocytes that were allowed to adhere to human microvascular endothelial cells. However, the expression of Foxp1 was not affected in monocytes that were treated with PKC delta-targeting small interfering RNA, suggesting that PKC delta regulates Foxp1 expression. These results demonstrate a role of PKC delta in alpha(M)beta(2)-mediated Foxp1 regulation in monocytes. The Journal of Immunology, 2010, 184: 3697-3709.