Src kinase activation by direct interaction with the integrin β cytoplasmic domain

Arias-Salgado, Elena G; Lizano, Sergio; Sarkar, Sugata; Brugge, Joan S.; Ginsberg, Mark H.; Shattil, Sanford J.

doi:10.1073/pnas.2336149100

Cited by 494 publications

(533 citation statements)

References 43 publications

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“…Src-family kinases can bind directly and specifically to individual integrin β tails [6]. For example, c-Src binds directly to the β3 tail and clustering β3 integrins increases Src activation [6].…”

Section: Discussionmentioning

confidence: 99%

“…These changes have been attributed to the regulation of cytoplasmic tyrosine kinases, FAK and Src, by integrins [9,10]. Both FAK and Src can bind directly to the integrin β tail [6,16]. Thus, Tac-β1 may titrate FAK and/or Src from endogenous β tails and prevent their activation by integrin engagement.…”

Section: Tac-β1 Inhibits the Adhesion-induced Phosphorylation Of Fakmentioning

confidence: 99%

“…These signals promote protrusion of the cell membrane during cell spreading to allow formation of new actin-associated adhesion sites [1]. The integrin β subunit cytoplasmic domain (β tail) contributes to these processes by linking integrins to the actin cytoskeleton and to intracellular signaling cascades [2][3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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Tac-β1 inhibits FAK activation and Src signaling

Berrier

Jones

LaFlamme

2008

Biochemical and Biophysical Research Communications

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The binding of integrins to extracellular matrix triggers signals that promote cell spreading. We previously demonstrated that expression of the integrin β1 cytoplasmic domain in the context of a chimeric transmembrane receptor with the Tac subunit of the interleukin-2 receptor (Tac-β1) inhibits cell spreading. To study the mechanism whereby Tac-β1-inhibits cell spreading, we examined the effect of Tac-β1 on early signaling events following integrin engagement namely FAK and Src signaling. We infected primary fibroblasts with adenoviruses expressing Tac or Tac-β1 and found that Tac-β1 prevented FAK activation by inhibiting the phosphorylation of FAK at Tyr-397. In contrast, Src activation was maintained, as phosphorylation of Src at Tyr-419 and Tyr-530 were not responsive to expression of Tac-β1. Importantly, adhesion-induced tyrosine phosphorylation of the Src substrates p130Cas and paxillin was inhibited, indicating that Src signaling was blocked by Tac-β1. These Src-dependent signaling events were found to require FAK signaling. Our results suggest that Tac-β1 inhibits cell spreading, at least in part, by preventing the phosphorylation of FAK at Tyr-397 and the assembly of signaling complexes necessary for phosphorylation of p130Cas and other downstream effectors.

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Section: Discussionmentioning

confidence: 99%

Section: Tac-β1 Inhibits the Adhesion-induced Phosphorylation Of Fakmentioning

confidence: 99%

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Tac-β1 inhibits FAK activation and Src signaling

Berrier

Jones

LaFlamme

2008

Biochemical and Biophysical Research Communications

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“…Loss of c-Src, in genetically deficient mouse models, leads to defects in ␤ 3 integrin signaling in platelets (10). For ␣ v ␤ 3 integrin signaling, the mechanism by which c-Src becomes activated during integrin signaling involves a direct interaction between the c-Src Src homology 3 domain and the C-terminal tail of the ␤ 3 chain (11). Clustering of ␤ 3 integrins in vivo activates c-Src leading to adhesion-dependent phosphorylation of Syk and other downstream signaling events.…”

mentioning

confidence: 99%

The Inhibitory Receptor PIR-B Negatively Regulates Neutrophil and Macrophage Integrin Signaling

Pereira

Zhang

Takai

et al. 2004

The Journal of Immunology

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The Ig-like receptor family member, PIR-B, has been shown to play an inhibitory role in receptor signaling within B cells, mast cells, and dendritic cells. As it has been implicated in integrin-mediated responses, we investigated the effect of loss of the PIR-B protein on integrin-mediated signaling in primary murine myeloid cells. The pir-b−/− neutrophils displayed enhanced respiratory burst, secondary granule release, and a hyperadhesive phenotype when plated on surfaces coated with either extracellular matrix proteins or cellular adhesion molecules in the presence or absence of the soluble inflammatory agonist TNF-α. The pir-b−/− and wild-type cells responded equivalently when stimulated with TNF-α in suspension, indicating that the hyperresponsive phenotype of the pir-b−/− cells during adhesion was due to enhanced integrin signaling. Both wild-type and pir-b−/− neutrophils expressed similar levels of integrin subunits. Primary bone marrow-derived macrophages from pir-b−/− mice were also hyperadhesive and spread more rapidly than wild-type cells following plating on surfaces that cross-linked cellular β2 integrins. Biochemical analysis of macrophages from pir-b−/− mice revealed enhanced phosphorylation and activation of proteins involved in integrin signaling. These observations point to a nonredundant role for PIR-B in the regulation of leukocyte integrin signaling.

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“…RhoA/ROCK-dependent inactivation of MLC phosphatase and phospholipase C (PLC)/Ca 2+ /calmodulin-dependent activation of MLC kinase (36). Interestingly, the RhoA activity can be suppressed by β3-associated Src catalyzing an activating phosphorylation of RhoA GAP (37), while the β1 cytoplasmic domain does not bind Src (38). This is consistent with lower RhoA activity after adhesion mediated by αvβ3 compared to α5β1 (39).…”

Section: Integrin Type-specific Signalsmentioning

confidence: 53%

Common and Diverging Integrin Signals Downstream of Adhesion and Mechanical Stimuli and Their Interplay with Reactive Oxygen Species

Zeller

Johansson

2014

Biophys. Rev. Lett.

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The integrin family of adhesion receptors regulates basic functions of cells, and the signals they induce are altered in tumor cells. In this review we discuss how different integrin-dependent signals are generated during cell adhesion and by physical forces acting on cells. We also describe how reactive oxygen species are integral parts of integrin signaling and highlight a few important questions in the field. Answers to those may improve our understanding of integrins and their role in the development of cancer.

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Src kinase activation by direct interaction with the integrin β cytoplasmic domain

Cited by 494 publications

References 43 publications

Tac-β1 inhibits FAK activation and Src signaling

Tac-β1 inhibits FAK activation and Src signaling

The Inhibitory Receptor PIR-B Negatively Regulates Neutrophil and Macrophage Integrin Signaling

Common and Diverging Integrin Signals Downstream of Adhesion and Mechanical Stimuli and Their Interplay with Reactive Oxygen Species

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