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Protease-activated receptor-induced Akt activation--regulation and possible function.
J Thromb Haemost. 2007 Dec; 5(12):2484-93.JT

Abstract

BACKGROUND

Thrombin induces the activation of the platelet serine/threonine kinase Akt. Akt activation is dependent on its phosphorylation at Thr308 and Ser473. The mechanism by which thrombin induces Akt phosphorylation is controversial, as is the role of Akt in platelet function.

OBJECTIVES

To investigate how protease-activated receptors (PARs) stimulate Akt and the role that Akt plays in human platelet function.

METHODS

Platelets were stimulated through PAR1 or PAR4. Specific inhibitors were used to evaluate, by Western blotting, signaling pathways regulating Akt phosphorylation, and the role of activated Akt was evaluated by aggregometry and flow cytometry.

RESULTS

Phospholipase C (PLC) controls Akt phosphorylation elicited by PARs. Stimulation of PAR1 or PAR4 resulted in rapid Akt phosphorylation, independently of secreted ADP and phosphatidylinositol-3-kinase (PI3K) activation. Akt phosphorylation approximately 60 s after PAR1 stimulation became entirely dependent on the purinergic receptor P2Y(12) and the activation of PI3K. In contrast, PAR4 partially sustained Akt phosphorylation independently of P2Y(12) and PI3K for up to 300 s. Pharmacologic inhibition of Akt reduced P-selectin expression and fibrinogen binding in platelets stimulated through PAR1, and delayed platelet aggregation in response to submaximal PAR1 or PAR4 stimulation, although aggregation at 300 s was unaffected.

CONCLUSIONS

Platelet PAR stimulation causes rapid Akt phosphorylation downstream of PLC, whereas with continuous stimulation, ADP and PI3K are required for maintaining Akt phosphorylation. Activated Akt regulates platelet function by modulating secretion and alpha(IIb)beta(3) activation.

Authors+Show Affiliations

Wihuri Research Institute, Kalliolinnantie 4, Helsinki, Finland. julio.resendiz@wri.fiNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17883592

Citation

Reséndiz, J C., et al. "Protease-activated Receptor-induced Akt Activation--regulation and Possible Function." Journal of Thrombosis and Haemostasis : JTH, vol. 5, no. 12, 2007, pp. 2484-93.
Reséndiz JC, Kroll MH, Lassila R. Protease-activated receptor-induced Akt activation--regulation and possible function. J Thromb Haemost. 2007;5(12):2484-93.
Reséndiz, J. C., Kroll, M. H., & Lassila, R. (2007). Protease-activated receptor-induced Akt activation--regulation and possible function. Journal of Thrombosis and Haemostasis : JTH, 5(12), 2484-93.
Reséndiz JC, Kroll MH, Lassila R. Protease-activated Receptor-induced Akt Activation--regulation and Possible Function. J Thromb Haemost. 2007;5(12):2484-93. PubMed PMID: 17883592.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protease-activated receptor-induced Akt activation--regulation and possible function. AU - Reséndiz,J C, AU - Kroll,M H, AU - Lassila,R, Y1 - 2007/09/19/ PY - 2007/9/22/pubmed PY - 2008/1/9/medline PY - 2007/9/22/entrez SP - 2484 EP - 93 JF - Journal of thrombosis and haemostasis : JTH JO - J Thromb Haemost VL - 5 IS - 12 N2 - BACKGROUND: Thrombin induces the activation of the platelet serine/threonine kinase Akt. Akt activation is dependent on its phosphorylation at Thr308 and Ser473. The mechanism by which thrombin induces Akt phosphorylation is controversial, as is the role of Akt in platelet function. OBJECTIVES: To investigate how protease-activated receptors (PARs) stimulate Akt and the role that Akt plays in human platelet function. METHODS: Platelets were stimulated through PAR1 or PAR4. Specific inhibitors were used to evaluate, by Western blotting, signaling pathways regulating Akt phosphorylation, and the role of activated Akt was evaluated by aggregometry and flow cytometry. RESULTS: Phospholipase C (PLC) controls Akt phosphorylation elicited by PARs. Stimulation of PAR1 or PAR4 resulted in rapid Akt phosphorylation, independently of secreted ADP and phosphatidylinositol-3-kinase (PI3K) activation. Akt phosphorylation approximately 60 s after PAR1 stimulation became entirely dependent on the purinergic receptor P2Y(12) and the activation of PI3K. In contrast, PAR4 partially sustained Akt phosphorylation independently of P2Y(12) and PI3K for up to 300 s. Pharmacologic inhibition of Akt reduced P-selectin expression and fibrinogen binding in platelets stimulated through PAR1, and delayed platelet aggregation in response to submaximal PAR1 or PAR4 stimulation, although aggregation at 300 s was unaffected. CONCLUSIONS: Platelet PAR stimulation causes rapid Akt phosphorylation downstream of PLC, whereas with continuous stimulation, ADP and PI3K are required for maintaining Akt phosphorylation. Activated Akt regulates platelet function by modulating secretion and alpha(IIb)beta(3) activation. SN - 1538-7933 UR - https://www.unboundmedicine.com/medline/citation/17883592/Protease_activated_receptor_induced_Akt_activation__regulation_and_possible_function_ L2 - https://doi.org/10.1111/j.1538-7836.2007.02769.x DB - PRIME DP - Unbound Medicine ER -