Differential regulation of actin stress fiber assembly and proplatelet formation by alpha2beta1 integrin and GPVI in human megakaryocytes.
The actin cytoskeleton plays a major role in platelet function. In contrast, its precise role in the function of megakaryocytes (MKs) is less understood but may be important for a chemoattractive response and an efficient proplatelet formation. In the marrow microenvironment, mature MKs are in contact with the extracellular matrix, including fibrillar collagen type I. MKs express alpha2beta1 integrin and the immunoglobulin superfamily member glycoprotein VI (GPVI), the main receptors for collagen. Using function-blocking antibodies or specific ligands, we investigated in primary human MKs how alpha2beta1 integrin and GPVI regulate stress fiber formation, the primary actin structures needed for cell contraction. Stress fiber assembly requires synergistic activation of the MAPK/Erk1/2 pathway and the small guanosine triphosphatase Rho via its effector, Rho-associated coiled-coil kinase (ROCK). alpha2beta1 integrin is crucial for stress fiber formation, whereas GPVI triggers rapid and sustained activation of the Erk1/2 pathway. Strikingly, after a longer adhesion time, proplatelet formation was significantly inhibited by the engagement of alpha2beta1 integrin, not by GPVI, likely through the Rho/ROCK pathway. Thus, proplatelet formation in human MKs could be tightly regulated by differential interactions with their collagen receptors. We propose that this interaction with collagen prevents proplatelet formation within the marrow.
Sabri
Siham
S
Institut National de la Santé et de la Recherche Médicale, U362, Institut Gustave Roussy, rue Camille Desmoulins, 94800 Villejuif, France. s.sabri@shaw.ca.
Jandrot-Perrus
Martine
M
Bertoglio
Jacques
J
Farndale
Richard W
RW
Mas
Véronique Mansat-De
VM
Debili
Najet
N
Vainchenker
William
W
D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000502:physiology; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D022502:Stress Fibers / Q000378:metabolism*; D054460:rho-Associated Kinases
D024042:Collagen Type I; D038982:Integrin alpha2beta1; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3