Abstract
The regulation of integrins expressed on leukocytes must be controlled precisely, and members of different integrin subfamilies have to act in concert to ensure the proper traffic of immune cells to sites of inflammation. The activation of β2 family integrins through the T cell receptor or by chemokines leads to the inactivation of very late antigen 4. The mechanism(s) of this cross-talk has not been known. We have now elucidated in detail how the signals are transmitted from leukocyte function-associated antigen 1 and show that, after its activation, the signaling involves specific phosphorylations of β2 integrin followed by interactions with cytoplasmic signaling proteins. This results in loss of β1 phosphorylation and a decrease in very late antigen 4 binding to its ligand vascular cell adhesion molecule 1. Our results show how a member of one integrin family regulates the activity of another integrin. This is important for the understanding of integrin-mediated processes.
Highlights
Integrins regulate leukocyte adhesion in a stepwise manner
Binding of J2.7 Cells to VCAM-1 through VLA-4 Can Be Blocked by LFA-1—For these studies, we mainly used the J2.7 Jurkat cell line, which contains a mutation in the ␣L gene, leading to lack of expression of ␣L and, no functional LFA-1 on the cell surface
To study how the expression of LFA-1 affects VLA-4, J2.7 cells, or LFA-1 cells were allowed to adhere to VCAM-1-coated wells and adhered cells were counted (Fig. 1B)
Summary
Integrins regulate leukocyte adhesion in a stepwise manner. Results: 2 Integrins can signal to 1 integrin very late antigen 4 and inhibit ligand binding. We have elucidated in detail how the signals are transmitted from leukocyte function-associated antigen 1 and show that, after its activation, the signaling involves specific phosphorylations of 2 integrin followed by interactions with cytoplasmic signaling proteins. This results in loss of 1 phosphorylation and a decrease in very late antigen 4 binding to its ligand vascular cell adhesion molecule 1. After both inside-out and outside-in activations, signaling is transmitted through 2 chain phosphorylation and the 14-3-3/ Tiam1/Rac pathway This results in the inhibition of 1 phosphorylation, VLA-4 binding to filamin, and inactivation of VLA-4
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