S6K1 and mTOR regulate Rac1-driven platelet activation and aggregation

Joseph Aslan, Garth W. Tormoen, Cassandra P. Loren, Jiaqing Pang, Owen McCarty

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Platelet activation and thrombus formation are under the control of signaling systems that integrate cellular homeostasis with cytoskeletal dynamics. Here, we identify a role for the ribosome protein S6 kinase (S6K1) and its upstream regulator mTOR in the control of platelet activation and aggregate formation under shear flow. Platelet engagement of fibrinogen initiated a signaling cascade that triggered the activation of S6K1 and Rac1. Fibrinogen-induced S6K1 activation was abolished by inhibitors of Src kinases, but not Rac1 inhibitors, demonstrating that S6K1 acts upstream of Rac1. S6K1 and Rac1 interacted in a protein complex with the Rac1 GEF TIAM1 and colocalized with actin at the platelet lamellipodial edge, suggesting that S6K1 and Rac1 work together to drive platelet spreading. Pharmacologic inhibitors of mTOR and S6K1 blocked Rac1 activation and prevented platelet spreading on fibrinogen, but had no effect on Src or FAK kinase activation. mTOR inhibitors dramatically reduced collageninduced platelet aggregation and promoted the destabilization of platelet aggregates formed under shear flow conditions. Together, these results reveal novel roles for S6K1 and mTOR in the regulation of Rac1 activity and provide insights into the relationship between the pharmacology of the mTOR system and the molecular mechanisms of platelet activation.

Original languageEnglish (US)
Pages (from-to)3129-3136
Number of pages8
JournalBlood
Volume118
Issue number11
DOIs
StatePublished - Sep 15 2011

Fingerprint

Platelet Activation
Platelets
Platelet Aggregation
Blood Platelets
Agglomeration
Chemical activation
Fibrinogen
Ribosomal Protein S6 Kinases
src-Family Kinases
Ribosomes
Shear flow
Protein Kinases
Actins
Thrombosis
Homeostasis
Phosphotransferases
Pharmacology
Proteins

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

S6K1 and mTOR regulate Rac1-driven platelet activation and aggregation. / Aslan, Joseph; Tormoen, Garth W.; Loren, Cassandra P.; Pang, Jiaqing; McCarty, Owen.

In: Blood, Vol. 118, No. 11, 15.09.2011, p. 3129-3136.

Research output: Contribution to journalArticle

Aslan, Joseph ; Tormoen, Garth W. ; Loren, Cassandra P. ; Pang, Jiaqing ; McCarty, Owen. / S6K1 and mTOR regulate Rac1-driven platelet activation and aggregation. In: Blood. 2011 ; Vol. 118, No. 11. pp. 3129-3136.
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