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Patel A , Kostyak J , Dangelmaier C , Badolia R , Bhavanasi D , Aslan JE , Merali S , Kim S , Eble JA , Goldfinger L , Kunapuli S
ELMO1 deficiency enhances platelet function
Blood Adv. 2019 Feb 26;3(4) :575-587
PMID: 30787021    PMCID: PMC6391667   
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Abstract
Phosphatidylinositol 3-kinase is an important signaling molecule that, once activated, leads to the generation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3). We performed a proteomic screen to identify PIP3-interacting proteins in human platelets. Among these proteins, we found engulfment and cell motility 1 (ELMO1), a scaffold protein with no catalytic activity. ELMO1 is expressed in platelets and interacts with active RhoG. However, the function of ELMO1 in platelets is not known. The focus of this study was to determine the function of ELMO1 in platelets utilizing ELMO1(-/-) mice. Platelet aggregation, granule secretion, integrin alphaIIbbeta3 activation, and thromboxane generation were enhanced in ELMO1(-/-) platelets in response to glycoprotein VI (GPVI) agonists but unaltered when a protease-activated receptor 4 agonist was used. The kinetics of spreading on immobilized fibrinogen was enhanced in ELMO1(-/-) platelets compared with wild-type (WT) littermate controls. This suggests that ELMO1 plays a role downstream of the GPVI and integrin alphaIIbbeta3 pathway. Furthermore, whole blood from ELMO1(-/-) mice perfused over collagen exhibited enhanced thrombus formation compared with WT littermate controls. ELMO1(-/-) mice showed reduced survival compared with control following pulmonary embolism. ELMO1(-/-) mice also exhibited a shorter time to occlusion using the ferric-chloride injury model and reduced bleeding times compared with WT littermate controls. These results indicate that ELMO1 plays an important role in hemostasis and thrombosis in vivo. RhoG activity was enhanced in ELMO1(-/-) murine platelets compared with WT littermate controls in response to GPVI agonist. Together, these data suggest that ELMO1 negatively regulates GPVI-mediated thrombus formation via RhoG.
Notes
2473-9537 Patel, Akruti Kostyak, John Dangelmaier, Carol Badolia, Rachit Bhavanasi, Dheeraj Aslan, Joseph E ORCID: http://orcid.org/0000-0002-8873-0387 Merali, Salim Kim, Soochong Eble, Johannes A Goldfinger, Lawrence Kunapuli, Satya R01 HL093231/HL/NHLBI NIH HHS/United States R01 HL132171/HL/NHLBI NIH HHS/United States R01 HL137207/HL/NHLBI NIH HHS/United States R01 HL137721/HL/NHLBI NIH HHS/United States Journal Article United States Blood Adv. 2019 Feb 26;3(4):575-587. doi: 10.1182/bloodadvances.2018016444.