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


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.


CONCLUSIONS
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.
Korporaal
Suzanne J A
SJ
Department of Clinical Chemistry and Haematology, University Medical Center, Utrecht, The Netherlands.
Koekman
C Arnold
CA
Verhoef
Sandra
S
van der Wal
Dianne E
DE
Bezemer
Martineke
M
Van Eck
Miranda
M
Akkerman
Jan-Willem N
JW
D000244:Adenosine Diphosphate / Q000378:metabolism; D001792:Blood Platelets / Q000201:enzymology*; D003094:Collagen / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D026502:LDL-Receptor Related Proteins; D008077:Lipoproteins, LDL / Q000378:metabolism*; D010766:Phosphorylation; D010974:Platelet Aggregation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D018110:Receptors, Lipoprotein / Q000378:metabolism; D018179:Receptors, Thrombin / Q000378:metabolism; D015398:Signal Transduction; D013928:Thromboxane A2 / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D026502:LDL-Receptor Related Proteins; D008077:Lipoproteins, LDL; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018110:Receptors, Lipoprotein; D018179:Receptors, Thrombin; C098773:low density lipoprotein receptor-related protein 8; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6