Detection of Bidirectional Signaling During Integrin Activation and Neutrophil Adhesion

New insights into the structural basis of integrin activation

Blood ◽

10.1182/blood-2003-01-0334 ◽

2003 ◽

Vol 102 (4) ◽

pp. 1155-1159 ◽

Cited By ~ 133

Author(s):

Jian-Ping Xiong ◽

Thilo Stehle ◽

Simon L. Goodman ◽

M. Amin Arnaout

Keyword(s):

Conformational Changes ◽

Structural Changes ◽

Structural Basis ◽

Integrin Activation ◽

Cellular Functions ◽

Electron Microscopic ◽

The Past ◽

Intracellular Signals ◽

Bidirectional Signaling ◽

New Hypothesis

Abstract Integrins are cell adhesion receptors that communicate biochemical and mechanical signals in a bidirectional manner across the plasma membrane and thus influence most cellular functions. Intracellular signals switch integrins into a ligand-competent state as a result of elicited conformational changes in the integrin ectodomain. Binding of extracellular ligands induces, in turn, structural changes that convey distinct signals to the cell interior. The structural basis of this bidirectional signaling has been the focus of intensive study for the past 3 decades. In this perspective, we develop a new hypothesis for integrin activation based on recent crystallographic, electron microscopic, and biochemical studies.

Download Full-text

Cytohesin-1 regulates human blood neutrophil adhesion to endothelial cells through β2 integrin activation

Molecular Immunology ◽

10.1016/j.molimm.2011.03.018 ◽

2011 ◽

Vol 48 (12-13) ◽

pp. 1408-1416 ◽

Cited By ~ 17

Author(s):

Mohammed-Amine El azreq ◽

Sylvain G. Bourgoin

Keyword(s):

Endothelial Cells ◽

Human Blood ◽

Neutrophil Adhesion ◽

Blood Neutrophil ◽

Integrin Activation ◽

Β2 Integrin

Download Full-text

Faculty Opinions recommendation of Radil controls neutrophil adhesion and motility through β2-integrin activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717968502.793468183 ◽

2012 ◽

Author(s):

Martin A Schwartz

Keyword(s):

Neutrophil Adhesion ◽

Integrin Activation ◽

Β2 Integrin

Download Full-text

Radil controls neutrophil adhesion and motility through β2-integrin activation

Molecular Biology of the Cell ◽

10.1091/mbc.e12-05-0408 ◽

2012 ◽

Vol 23 (24) ◽

pp. 4751-4765 ◽

Cited By ~ 15

Author(s):

Lunhua Liu ◽

Wulin Aerbajinai ◽

Syed M. Ahmed ◽

Griffin P. Rodgers ◽

Stephane Angers ◽

...

Keyword(s):

Cell Adhesion ◽

Inflammatory Responses ◽

Neutrophil Adhesion ◽

Dependent Manner ◽

Neutrophil Chemotaxis ◽

Integrin Activation ◽

Chemotactic Migration ◽

Long Tail ◽

Β2 Integrin ◽

Inhibitory Antibodies

Integrin activation is required to facilitate multiple adhesion-dependent functions of neutrophils, such as chemotaxis, which is critical for inflammatory responses to injury and pathogens. However, little is known about the mechanisms that mediate integrin activation in neutrophils. We show that Radil, a novel Rap1 effector, regulates β1- and β2-integrin activation and controls neutrophil chemotaxis. On activation and chemotactic migration of neutrophils, Radil quickly translocates from the cytoplasm to the plasma membrane in a Rap1a-GTP–dependent manner. Cells overexpressing Radil show a substantial increase in cell adhesion, as well as in integrin/focal adhesion kinase (FAK) activation, and exhibit an elongated morphology, with severe tail retraction defects. This phenotype is effectively rescued by treatment with either β2-integrin inhibitory antibodies or FAK inhibitors. Conversely, knockdown of Radil causes severe inhibition of cell adhesion, β2-integrin activation, and chemotaxis. Furthermore, we found that inhibition of Rap activity by RapGAP coexpression inhibits Radil-mediated integrin and FAK activation, decreases cell adhesion, and abrogates the long-tail phenotype of Radil cells. Overall, these studies establish that Radil regulates neutrophil adhesion and motility by linking Rap1 to β2-integrin activation.

Download Full-text

Critical roles for the COOH-terminal NITY and RGT sequences of the integrin β3 cytoplasmic domain in inside-out and outside-in signaling

The Journal of Cell Biology ◽

10.1083/jcb.200303120 ◽

2003 ◽

Vol 162 (2) ◽

pp. 329-339 ◽

Cited By ~ 46

Author(s):

Xiaodong Xi ◽

Richard J. Bodnar ◽

Zhenyu Li ◽

Stephen C.-T. Lam ◽

Xiaoping Du

Keyword(s):

Cytoplasmic Domain ◽

Integrin Signaling ◽

Integrin Activation ◽

Calcium Dependent ◽

Fibrinogen Binding ◽

Bidirectional Signaling ◽

Platelet Receptor ◽

Von Willebrand ◽

Willebrand Factor ◽

Inside Out

Bidirectional signaling of integrin αIIbβ3 requires the β3 cytoplasmic domain. To determine the sequence in the β3 cytoplasmic domain that is critical to integrin signaling, cell lines were established that coexpress the platelet receptor for von Willebrand factor (vWF), glycoprotein Ib-IX, integrin αIIb, and mutants of β3 with truncations at sites COOH terminal to T741, Y747, F754, and Y759. Truncation at Y759 did not affect integrin activation, as indicated by vWF-induced fibrinogen binding, but affected cell spreading and stable adhesion. Thus, the COOH-terminal RGT sequence of β3 is important for outside-in signaling but not inside-out signaling. In contrast, truncation at F754, Y747, or T741 completely abolished integrin activation. A point mutation replacing Y759 with alanine also abolished integrin activation. Thus, the T755NITY759 sequence of β3, containing an NXXY motif, is critical to inside-out signaling, whereas the intact COOH terminus is important for outside-in signaling. In addition, we found that the calcium-dependent protease calpain preferentially cleaves at Y759 in a population of β3 during platelet aggregation and adhesion, suggesting that calpain may selectively regulate integrin outside-in signaling.

Download Full-text