ELMO1 deficiency enhances platelet function

Akruti Patel, John Kostyak, Carol Dangelmaier, Rachit Badolia, Dheeraj Bhavanasi, Joseph Aslan, Salim Merali, Soochong Kim, Johannes A. Eble, Lawrence Goldfinger, Satya Kunapuli

Research output: Contribution to journalArticle

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 αIIbβ3 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 αIIbβ3 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.

Original languageEnglish (US)
Pages (from-to)575-587
Number of pages13
JournalBlood advances
Volume3
Issue number4
DOIs
StatePublished - Feb 26 2019

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Cell Movement
Blood Platelets
Glycoproteins
Thrombosis
Integrins
Phosphatidylinositol 3-Kinase
Proteins
Bleeding Time
Thromboxanes
Hemostasis
Pulmonary Embolism
Platelet Aggregation
Proteomics
Fibrinogen
Blood Cells
Collagen

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Patel, A., Kostyak, J., Dangelmaier, C., Badolia, R., Bhavanasi, D., Aslan, J., ... Kunapuli, S. (2019). ELMO1 deficiency enhances platelet function. Blood advances, 3(4), 575-587. https://doi.org/10.1182/bloodadvances.2018016444

ELMO1 deficiency enhances platelet function. / Patel, Akruti; Kostyak, John; Dangelmaier, Carol; Badolia, Rachit; Bhavanasi, Dheeraj; Aslan, Joseph; Merali, Salim; Kim, Soochong; Eble, Johannes A.; Goldfinger, Lawrence; Kunapuli, Satya.

In: Blood advances, Vol. 3, No. 4, 26.02.2019, p. 575-587.

Research output: Contribution to journalArticle

Patel, A, Kostyak, J, Dangelmaier, C, Badolia, R, Bhavanasi, D, Aslan, J, Merali, S, Kim, S, Eble, JA, Goldfinger, L & Kunapuli, S 2019, 'ELMO1 deficiency enhances platelet function', Blood advances, vol. 3, no. 4, pp. 575-587. https://doi.org/10.1182/bloodadvances.2018016444
Patel A, Kostyak J, Dangelmaier C, Badolia R, Bhavanasi D, Aslan J et al. ELMO1 deficiency enhances platelet function. Blood advances. 2019 Feb 26;3(4):575-587. https://doi.org/10.1182/bloodadvances.2018016444
Patel, Akruti ; Kostyak, John ; Dangelmaier, Carol ; Badolia, Rachit ; Bhavanasi, Dheeraj ; Aslan, Joseph ; Merali, Salim ; Kim, Soochong ; Eble, Johannes A. ; Goldfinger, Lawrence ; Kunapuli, Satya. / ELMO1 deficiency enhances platelet function. In: Blood advances. 2019 ; Vol. 3, No. 4. pp. 575-587.
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