Structural framework of c-Src activation by integrin β3

Xiao, Run; Xi, Xiaodong; Zhu, Chen; Chen, Sai‐Juan; Meng, Guoyu

doi:10.1182/blood-2012-07-440644

Cited by 22 publications

(21 citation statements)

References 37 publications

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“…Deletion of Src in mouse platelets reduces spreading on fibrinogen independently of other Src-family kinases, but Src is not necessary for the aggregation of platelets under flow conditions (Séverin et al, 2012). Src activation through Tyr 416 phosphorylation can be achieved by several mechanisms, although the data presented here revealed enhanced interactions with the b 3 cytoplasmic domain (Arias-Salgado et al, 2003Xiao et al, 2013). c-Src interacts with the last three residues in the intracellular carboxy-terminal tail of integrin b 3 , typically after activation of aIIbb 3 and talin binding.…”

Section: Discussioncontrasting

confidence: 42%

“…c-Src interacts with the last three residues in the intracellular carboxy-terminal tail of integrin b 3 , typically after activation of aIIbb 3 and talin binding. This interaction, albeit a low-affinity one, is sufficient to disrupt the interaction between c-Src SH3 domain and its kinase domain, promoting c-Src activation (Xiao et al, 2013). Our data indicate enhanced talin binding, which may "free" the Src-interacting RGT tail of b 3 , thus facilitating Src activation.…”

Section: Discussionmentioning

confidence: 70%

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Pro32Pro33 Mutations in the Integrin β3 PSI Domain Result in αIIbβ3 Priming and Enhanced Adhesion: Reversal of the Hypercoagulability Phenotype by the Src Inhibitor SKI-606

Oliver¹,

Jessen²,

Crawford³

et al. 2014

Molecular Pharmacology

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The plasma-membrane integrin aIIbb 3 (CD41/CD61, GPIIbIIIa) is a major functional receptor in platelets during clotting. A common isoform of integrin b 3 , Leu33Pro is associated with enhanced platelet function and increased risk for coronary thrombosis and stroke, although these findings remain controversial. To better understand the molecular mechanisms by which this sequence variation modifies platelet function, we produced transgenic knockin mice expressing a Pro32Pro33 integrin b 3 . Consistent with reports utilizing human platelets, we found significantly reduced bleeding and clotting times, as well as increased in vivo thrombosis, in Pro32Pro33 homozygous mice. These alterations paralleled increases in platelet attachment and spreading onto fibrinogen resulting from enhanced integrin aIIbb 3 function. Activation with protease-activated receptor 4-activating peptide, the main thrombin signaling receptor in mice, showed no significant difference in activation of Pro32Pro33 mice as compared with controls, suggesting that inside-out signaling remains intact. However, under unstimulated conditions, the Pro32Pro33 mutation led to elevated Src phosphorylation, facilitated by increased talin interactions with the b 3 cytoplasmic domain, indicating that the aIIbb 3 intracellular domains are primed for activation while the ligand-binding domain remains unchanged. Acute dosing of animals with a Src inhibitor was sufficient to rescue the clotting phenotype in knockin mice to wild-type levels. Together, our data establish that the Pro32Pro33 structural alteration modifies the function of integrin aIIbb 3 , priming the integrin for outside-in signaling, ultimately leading to hypercoagulability. Furthermore, our data may support a novel approach to antiplatelet therapy by Src inhibition where hemostasis is maintained while reducing risk for cardiovascular disease.

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Section: Discussioncontrasting

confidence: 42%

Section: Discussionmentioning

confidence: 70%

Pro32Pro33 Mutations in the Integrin β3 PSI Domain Result in αIIbβ3 Priming and Enhanced Adhesion: Reversal of the Hypercoagulability Phenotype by the Src Inhibitor SKI-606

Oliver¹,

Jessen²,

Crawford³

et al. 2014

Molecular Pharmacology

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“…Initial structural analyses of the b3 tail in complex with the c-Src SH3 domain have been conducted. 65 Analogous studies of the b3 tail in complex with kindlins could shed more light on the feasibility of such a therapeutic approach. Figure 5C).…”

Section: Org Frommentioning

confidence: 99%

Interaction of kindlin-2 with integrin β3 promotes outside-in signaling responses by the αVβ3 vitronectin receptor

Liao

Kato

Pandey

et al. 2015

Blood

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“…Then, the recombinant proteins His-HSP90a and His-HSP90b expressed in BL21 bacteria were purified according to the protocol in our previous work (26).…”

Section: Preparation Of Recombinant Proteinsmentioning

confidence: 99%

Vibsanin B Preferentially Targets HSP90β, Inhibits Interstitial Leukocyte Migration, and Ameliorates Experimental Autoimmune Encephalomyelitis

Deng

Shao

et al. 2015

The Journal of Immunology

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Interstitial leukocyte migration plays a critical role in inflammation and offers a therapeutic target for treating inflammation-associated diseases such as multiple sclerosis. Identifying small molecules to inhibit undesired leukocyte migration provides promise for the treatment of these disorders. In this study, we identified vibsanin B, a novel macrocyclic diterpenoid isolated from Viburnum odoratissimum Ker-Gawl, that inhibited zebrafish interstitial leukocyte migration using a transgenic zebrafish line (TG:zlyz–enhanced GFP). We found that vibsanin B preferentially binds to heat shock protein (HSP)90β. At the molecular level, inactivation of HSP90 can mimic vibsanin B’s effect of inhibiting interstitial leukocyte migration. Furthermore, we demonstrated that vibsanin B ameliorates experimental autoimmune encephalomyelitis in mice with pathological manifestation of decreased leukocyte infiltration into their CNS. In summary, vibsanin B is a novel lead compound that preferentially targets HSP90β and inhibits interstitial leukocyte migration, offering a promising drug lead for treating inflammation-associated diseases.

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Structural framework of c-Src activation by integrin β3

Abstract: Key Points• Crystal structure of SH3:RGT complex reveals how integrin ␤3 primes/activates c-Src kinase.

Cited by 22 publications

References 37 publications

Pro32Pro33 Mutations in the Integrin β3 PSI Domain Result in αIIbβ3 Priming and Enhanced Adhesion: Reversal of the Hypercoagulability Phenotype by the Src Inhibitor SKI-606

Pro32Pro33 Mutations in the Integrin β3 PSI Domain Result in αIIbβ3 Priming and Enhanced Adhesion: Reversal of the Hypercoagulability Phenotype by the Src Inhibitor SKI-606

Interaction of kindlin-2 with integrin β3 promotes outside-in signaling responses by the αVβ3 vitronectin receptor

Vibsanin B Preferentially Targets HSP90β, Inhibits Interstitial Leukocyte Migration, and Ameliorates Experimental Autoimmune Encephalomyelitis

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