Specific Phosphorylations Transmit Signals from Leukocyte β2 to β1 Integrins and Regulate Adhesion

Uotila, Liisa M.; Jahan, Farhana; Hinojosa, Laura Soto; Melandri, Emiliano; Grönholm, Mikaela; Gahmberg, Carl G.

doi:10.1074/jbc.m114.588111

Cited by 20 publications

(27 citation statements)

References 41 publications

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“…We have previously shown that activation of LFA-1 through the TCR receptor or chemokine receptors, induces a signaling pathway, leading to the phosphorylation of Thr-758 on the b 2 -chain, 14-3-3 and Tiam1 binding, [14][15][16]19 and downregulation of a 4 b 1 binding to VCAM-1. 13 We have now found that activating and inhibitory antibodies to LFA-1 can regulate this signaling pathway. We collected antibodies to both b 2 and a L , which have been described to activate, inhibit, or have no effect on LFA-1 ligand binding (Table 1).…”

Section: Cell Adhesion and Migration Assaysmentioning

confidence: 92%

“…Jb2.7 expressing wt LFA-1 has been described. 13 Naive T cells were purified from buffy coats obtained from the Finnish Red Cross Blood Transfusion Service (Helsinki, Finland) by Ficoll-Hypaque gradient centrifugation and nylon-wool columns. T blasts were induced by ImmunoCult human CD3/CD28/CD2 T-cell activator and 30 IU/mL IL-2 in ImmunoCult-XF T Cell Expansion Medium (Stemcell Technologies, Grenoble, France) and used after 96 hours.…”

Section: Cell Cultures Immunoprecipitation and Immunoblottingmentioning

confidence: 99%

“…11 We and others have previously shown that TCR activation, chemokines, and ligands to LFA-1 regulate a 4 b 1 activity in T cells. 12,13 Changes in both the phosphorylation status of b 1 and b 2 chains and the b-chain binding proteins mediate this crosstalk. 13 The signaling pathway from the phosphorylated Thr-758 in the b 2 integrin, followed by 14-3-3 binding, recruitment of T-cell lymphoma invasion and metastasis 1 (Tiam1) protein, and upregulation of Ras-related C3 botulinum toxin substrate 1 (Rac1) was described earlier.…”

mentioning

confidence: 99%

“…12,13 Changes in both the phosphorylation status of b 1 and b 2 chains and the b-chain binding proteins mediate this crosstalk. 13 The signaling pathway from the phosphorylated Thr-758 in the b 2 integrin, followed by 14-3-3 binding, recruitment of T-cell lymphoma invasion and metastasis 1 (Tiam1) protein, and upregulation of Ras-related C3 botulinum toxin substrate 1 (Rac1) was described earlier. [14][15][16] This leads to dephosphorylation of b 1 Thr-788/789, reduced b 1 -14-3-3 binding, increased filamin binding to b 1 , and reduced adhesion of cells to VCAM-1.…”

mentioning

confidence: 99%

“…[14][15][16] This leads to dephosphorylation of b 1 Thr-788/789, reduced b 1 -14-3-3 binding, increased filamin binding to b 1 , and reduced adhesion of cells to VCAM-1. 13 We have now studied the effect of LFA-1-specific antibodies on cross-talk to a 4 b 1 . We show that activating and some blocking LFA-1 antibodies inhibit a 4 b 1 -binding to VCAM-1.…”

mentioning

confidence: 99%

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LFA-1 integrin antibodies inhibit leukocyte α4β1–mediated adhesion by intracellular signaling

Grönholm

Jahan

Bryushkova

et al. 2016

Blood

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Key Points• Activating and inhibitory antibodies to the LFA-1 integrin inhibit the a 4 b 1 integrin.• Inhibition occurs by intracellular signaling resulting from integrin phosphorylations.Binding of intercellular adhesion molecule-1 to the b 2 -integrin leukocyte function associated antigen-1 (LFA-1) is known to induce cross-talk to the a 4 b 1 integrin. Using different LFA-1 monoclonal antibodies, we have been able to study the requirement and mechanism of action for the cross-talk in considerable detail. LFA-1-activating antibodies and those inhibitory antibodies that signal to a 4 b 1 induce phosphorylation of Thr-758 on the b 2 -chain, which is followed by binding of 14-3-3 proteins and signaling through the G protein exchange

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Section: Cell Adhesion and Migration Assaysmentioning

confidence: 92%

Section: Cell Cultures Immunoprecipitation and Immunoblottingmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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LFA-1 integrin antibodies inhibit leukocyte α4β1–mediated adhesion by intracellular signaling

Grönholm

Jahan

Bryushkova

et al. 2016

Blood

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Lymphocyte integrin expression differences between SIRS and sepsis patients

2016

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Background Systemic Inflammatory Response Syndrome (SIRS) and sepsis remain leading causes of death. Despite many similarities, the 2 entities are very distinct clinically and immunologically. T-Lymphocytes play a key pivotal role in the pathogenesis and ultimately outcomes following both SIRS and sepsis. Integrins are essential in the trafficking and migration of lymphocytes. They also serve vital roles in efficient wound healing and clearance of infections. Here, we investigate whether integrin expression, specifically β1 (CD29) and β2 (CD18), are disrupted in SIRS and sepsis, and assess differences in integrin expression between these 2 critically ill clinical categories. Methods T-Lymphocytes were isolated from whole blood collected from ICU patients exhibiting SIRS or sepsis. Samples were analyzed for CD18 (β2) and CD29 (β1) on CD3+ T cells through flow cytometry. Septic patients were stratified into either exclusively abdominal or non-abdominal source of sepsis. Results CD18 was almost ubiquitously expressed on CD3+ T cells irrespective of clinical condition. However, CD29 (β1 integrin) was lowest in SIRS patients (20.4% of CD3+ T-cells) when compared with either septic patients (35.5%) or healthy volunteers (54.1%). Further, there was evidence of compartmentalization in septic patients, where abdominal sources had a greater percentage of CD3+CD29+ T-cells (41.7%) when compared with those with non-abdominal sources (29.5%). Conclusion Distinct differences in T-cell integrin expression exists between patients in SIRS versus sepsis, as well as relative to the source of sepsis. Further work is needed to understand cause and effect relative to the progression from SIRS into sepsis.

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How integrin phosphorylations regulate cell adhesion and signaling

Gahmberg

Grönholm

2022

Trends in Biochemical Sciences

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Cell adhesion is essential for the formation of organs, cellular migration, and interaction with target cells and the extracellular matrix. Integrins are large protein α/β-chain heterodimers and form a major family of cell adhesion molecules. Recent research has dramatically increased our knowledge of how integrin phosphorylations regulate integrin activity. Phosphorylations determine the signaling complexes formed on the cytoplasmic tails, regulating downstream signaling. α-Chain phosphorylation is necessary for inducing β-chain phosphorylation in LFA-1, and the crosstalk from one integrin to another activating or inactivating its function is in part mediated by phosphorylation of β-chains. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus receptor angiotensin-converting enzyme 2 (ACE2) and possible integrin coreceptors may crosstalk and induce a phosphorylation switch and autophagy.

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Specific Phosphorylations Transmit Signals from Leukocyte β2 to β1 Integrins and Regulate Adhesion

Cited by 20 publications

References 41 publications

LFA-1 integrin antibodies inhibit leukocyte α4β1–mediated adhesion by intracellular signaling

LFA-1 integrin antibodies inhibit leukocyte α4β1–mediated adhesion by intracellular signaling

Lymphocyte integrin expression differences between SIRS and sepsis patients

How integrin phosphorylations regulate cell adhesion and signaling

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