| First Author | Borst O | Year | 2012 |
| Journal | Blood | Volume | 119 |
| Issue | 1 | Pages | 251-61 |
| PubMed ID | 22031864 | Mgi Jnum | J:181576 |
| Mgi Id | MGI:5311990 | Doi | 10.1182/blood-2011-06-359976 |
| Citation | Borst O, et al. (2012) The serum- and glucocorticoid-inducible kinase 1 (SGK1) influences platelet calcium signaling and function by regulation of Orai1 expression in megakaryocytes. Blood 119(1):251-61 |
| abstractText | Platelets are activated on increase of cytosolic Ca2+ activity ([Ca2+](i)), accomplished by store-operated Ca2+ entry (SOCE) involving the pore-forming ion channel subunit Orai1. Here, we show, for the first time, that the serum- and glucocorticoid-inducible kinase 1 (SGK1) is expressed in platelets and megakaryocytes. SOCE and agonist-induced [Ca2+](i) increase are significantly blunted in platelets from SGK1 knockout mice (sgk1(-/-)). Similarly, Ca2+ -dependent degranulation, integrin alpha(IIb)beta3 activation, phosphatidylserine exposure, aggregation, and in vitro thrombus formation were significantly impaired in sgk1(-/-) platelets, whereas tail bleeding time was not significantly enhanced. Platelet and megakaryocyte Orai1 transcript levels and membrane protein abundance were significantly reduced in sgk1(-/-) mice. In human megakaryoblastic cells (MEG-01), transfection with constitutively active (S422D)SGK1 but not with inactive (K127N)SGK1 significantly enhanced Orai1 expression and SOCE, while effects reversed by the SGK1 inhibitor GSK650394 (1muM). Transfection of MEG-01 cells with (S422D)SGK1 significantly increased phosphorylation of IkappaB kinase alpha/beta and IkappaBalpha resulting in nuclear translocation of NF-kappaB subunit p65. Treatment of (S422D)SGK1-transfected MEG-01 cells with the IkappaB kinase inhibitor BMS-345541 (10muM) abolished SGK1-induced increase of Orai1 expression and SOCE. The present observations unravel SGK1 as novel regulator of platelet function, effective at least in part by NF-kappaB-dependent transcriptional up-regulation of Orai1 in megakaryocytes and increasing platelet SOCE. |
