Downregulation of platelet responsiveness upon contact with LDL by the protein-tyrosine phosphatases SHP-1 and SHP-2

Suzanne Korporaal, C.A. Koekman, Sandra Verhoef, van der Wal DE, Martineke Bezemer, Miranda Van Eck, Jan Willem N Akkerman*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)


OBJECTIVE: The sensitivity of platelets to aggregating agents increases when low-density lipoprotein (LDL) binds to apolipoprotein E receptor 2' (apoER2'), triggering activation of p38MAPK and formation of thromboxane A2. LDL signaling is terminated by PECAM-1 through recruitment and activation of the Ser/Thr protein phosphatase PP2A, but platelets remain unresponsive to LDL when PECAM-1 activation disappears. We report a second mechanism that halts LDL signaling and in addition lowers platelet responsiveness to aggregating agents.
METHODS AND RESULTS: After a first stimulation with LDL, platelets remain unresponsive to LDL for 60 minutes, despite normal apoER2' activation by a second dose of LDL. A possible cause is persistent activation of the tyrosine phosphatases SHP-1 and SHP-2, which may not only block a second activation of p38MAPK, PECAM-1, and PP2A by LDL but also seem to reduce aggregation by TRAP, collagen, and ADP.
CONCLUSION: These findings reveal that p38MAPK phosphorylation and platelet activation by LDL are suppressed by two mechanisms: (1) short activation of PECAM-1/PP2A, and (2) prolonged activation of SHP-1 and SHP-2. Activation of SHP-1 and SHP-2 is accompanied by reduced responsiveness to aggregating agents, which--if present in vivo--would make LDL an aggregation inhibitor during prolonged contact with platelets.
Original languageEnglish
Pages (from-to)372-379
Number of pages8
JournalArteriosclerosis, Thrombosis and Vascular Biology
Issue number3
Publication statusPublished - 1 Mar 2009


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