| First Author | Consonni A | Year | 2012 |
| Journal | Blood | Volume | 119 |
| Issue | 3 | Pages | 847-56 |
| PubMed ID | 22106345 | Mgi Jnum | J:181791 |
| Mgi Id | MGI:5314183 | Doi | 10.1182/blood-2011-07-364992 |
| Citation | Consonni A, et al. (2012) Role and regulation of phosphatidylinositol 3-kinase beta in platelet integrin alpha2beta1 signaling. Blood 119(3):847-56 |
| abstractText | Integrin alpha2beta1-mediated adhesion of human platelets to monomeric type I collagen or to the GFOGER peptide caused a time-dependent activation of PI3K and Akt phosphorylation. This process was abrogated by pharmacologic inhibition of PI3Kbeta, but not of PI3Kgamma or PI3Kalpha. Moreover, Akt phosphorylation was undetectable in murine platelets expressing a kinase-dead mutant of PI3Kbeta (PI3Kbeta(KD)), but occurred normally in PI3Kgamma(KD) platelets. Integrin alpha2beta1 failed to stimulate PI3Kbeta in platelets from phospholipase Cgamma2 (PLCgamma2)-knockout mice, and we found that intracellular Ca(2+) linked PLCgamma2 to PI3Kbeta activation. Integrin alpha2beta1 also caused a time-dependent stimulation of the focal kinase Pyk2 downstream of PLCgamma2 and intracellular Ca(2+). Whereas activation of Pyk2 occurred normally in PI3Kbeta(KD) platelets, stimulation of PI3Kbeta was strongly reduced in Pyk2-knockout mice. Neither Pyk2 nor PI3Kbeta was required for alpha2beta1-mediated adhesion and spreading. However, activation of Rap1b and inside-out stimulation of integrin alphaIIbbeta3 were reduced after inhibition of PI3Kbeta and were significantly impaired in Pyk2-deficient platelets. Finally, both PI3Kbeta and Pyk2 significantly contributed to thrombus formation under flow. These results demonstrate that Pyk2 regulates PI3Kbeta downstream of integrin alpha2beta1, and document a novel role for Pyk2 and PI3Kbeta in integrin alpha2beta1 promoted inside-out activation of integrin alphaIIbbeta3 and thrombus formation. |
