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G(12/13) signaling pathways substitute for integrin αIIbβ3-signaling for thromboxane generation in platelets

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Published copy (DOI)

Author(s)

  • Kamala Bhavaraju
  • Parth R Lakhani
  • Robert T Dorsam
  • Jianguo Jin
  • Ian S Hitchcock
  • Archana Sanjay
  • Satya P Kunapuli

Department/unit(s)

Publication details

JournalPLoS ONE
DatePublished - 2011
Issue number2
Volume6
Pages (from-to)e16586
Original languageEnglish

Abstract

BACKGROUND: We have previously shown that ADP-induced TXA(2) generation requires signaling from αIIbβ3 integrin in platelets. Here we observed that, unlike ADP, protease-activated receptor (PAR)-mediated TXA(2) generation occurs independently of αIIbβ3. PAR agonists, but not ADP, activate G(12/13) signaling pathways. Hence, we evaluated the role of these pathways in TXA(2) generation.

PRINCIPAL FINDINGS: Inhibition of ADP-induced thromboxane generation by fibrinogen receptor antagonist SC57101 was rescued by co-stimulation of G(12/13) pathways with YFLLRNP. This observation suggested an existence of a common signaling effector downstream of integrins and G(12/13) pathways. Hence, we evaluated role of three potential tyrosine kinases; c-Src, Syk and FAK (Focal Adhesion Kinase) that are known to be activated by integrins. c-Src and Syk kinase did not play a role in ADP-induced functional responses in platelets. Selective activation of G(12/13) pathways resulted in the activation of FAK, in the absence of integrin signaling. Interestingly, αIIbβ3-mediated FAK activation occurred in a Src family kinase (SFK)-independent manner whereas G(12/13) pathway caused FAK activation in a SFK and RhoA-dependent manner. A FAK selective inhibitor TAE-226, blocked TXA(2) generation. However, in comparison to WT mice, Pf4-Cre/Fak-Floxed mice did not show any difference in platelet TXA(2) generation.

CONCLUSIONS: Therefore, we conclude that differential activation of FAK occurs downstream of Integrins and G(12/13) pathways. However, the common effector molecule, possibly a tyrosine kinase downstream of integrins and G(12/13) pathways contributing to TXA(2) generation in platelets remains elusive.

    Research areas

  • Adenosine Diphosphate, Animals, Blood Platelets, Enzyme Activation, Focal Adhesion Protein-Tyrosine Kinases, GTP-Binding Protein alpha Subunits, G12-G13, Humans, Intracellular Signaling Peptides and Proteins, Mice, Platelet Glycoprotein GPIIb-IIIa Complex, Protein-Tyrosine Kinases, Proto-Oncogene Proteins pp60(c-src), Signal Transduction, Thromboxane A2, rho-Associated Kinases

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