Integrin-dependent Control of Translation: Engagement of Integrin αIIbβ3 Regulates Synthesis of Proteins in Activated Human Platelets

Abstract

Integrins are widely expressed plasma membrane adhesion molecules that tether cells to matrix proteins and to one another in cell–cell interactions. Integrins also transmit outside-in signals that regulate functional responses of cells, and are known to influence gene expression by regulating transcription. In previous studies we found that platelets, which are naturally occurring anucleate cytoplasts, translate preformed mRNA transcripts when they are activated by outside-in signals. Using strategies that interrupt engagement of integrin αIIbβ3 by fibrinogen and platelets deficient in this integrin, we found that αIIbβ3 regulates the synthesis of B cell lymphoma 3 (Bcl-3) when platelet aggregation is induced by thrombin. We also found that synthesis of Bcl-3, which occurs via a specialized translation control pathway regulated by mammalian target of rapamycin (mTOR), is induced when platelets adhere to immobilized fibrinogen in the absence of thrombin and when integrin αIIbβ3 is engaged by a conformation-altering antibody against integrin αIIbβ3. Thus, outside-in signals delivered by integrin αIIbβ3 are required for translation of Bcl-3 in thrombin-stimulated aggregated platelets and are sufficient to induce translation of this marker protein in the absence of thrombin. Engagement of integrin α2β1 by collagen also triggered synthesis of Bcl-3. Thus, control of translation may be a general mechanism by which surface adhesion molecules regulate gene expression.

Activation of tumor cell integrin α v β 3 controls angiogenesis and metastatic growth in the brain

“…Several integrins, including ␣ 6 ␤ 4 , ␣ IIb ␤ 3 , and ␣ 2 ␤ 1 , can promote translation of weak mRNAs through the PI3K-Akt-mTOR pathway (31,32). In contrast, activation of integrin ␣ v ␤ 3 did not result in enhanced activation of mTOR or Akt in brain lesions, suggesting that a different mechanism is involved.…”

Fibronectin controls cap-dependent translation through β1 integrin and eukaryotic initiation factors 4 and 2 coordinated pathways

“…Effects of adhesion on translation were described for other substrates (27)(28)(29) showing the importance of mTOR and eIF4E relocalization. We found that FN induces translation through eIF4F with a marginal involvement of the mTOR pathway, and, consistently, without stimulating TOP mRNA translation (see model in Fig.…”

“…The effect of adhesion to ECM on translation has been addressed in models requiring ␤3 integrin (27,28) or ␤4 integrin (29) and in platelets (30). These studies showed the importance of the activation of mTOR in adhesion-regulated translation.…”

The Cap-Dependent Translation Apparatus Integrates and Amplifies Cancer Pathways

“…[66][67][68][69] Upregulated cap-dependent translation liberates cells from strict dependence on adhesion. For example, ectopic eIF4E converts immortalized HMECs into cells that form colonies when cultured at low density on a plastic substratum or in soft agar, 57 but does not by itself enable tumorigenicity.…”