Negative regulation of activated alpha-2 integrins during thrombopoiesis.
Circulating platelets exhibit rapid signaling and adhesive responses to collagen that facilitate hemostasis at sites of vessel injury. Because platelets are anuclear, their collagen receptors must be expressed by megakaryocytes, platelet precursors that arise in the collagen-rich environment of the bone marrow. Whether and how megakaryocytes regulate collagen adhesion during their development in the bone marrow are unknown. We find that surface expression of activated, but not wild-type, alpha2 integrins in hematopoietic cells in vivo results in the generation of platelets that lack surface alpha2 receptors. Culture of hematopoietic progenitor cells ex vivo reveals that surface levels of activated, but not wild-type, alpha2 integrin receptors are rapidly down-regulated during cell growth on collagen but reach wild-type levels when cells are grown in the absence of collagen. Progenitor cells that express activated alpha2 integrins are normally distributed in the bone marrow in vivo and exhibit normal migration across a collagen-coated membrane ex vivo. This migration is accompanied by rapid down-regulation of activated surface integrins. These studies identify ligand-dependent removal of activated alpha2 receptors from the cell surface as a mechanism by which integrin function can be negatively regulated in hematopoietic cells during migration between the adhesive environment of the bone marrow and the nonadhesive environment of the circulating blood.
Zou
Zhiying
Z
Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, 19104, USA.
Schmaier
Alec A
AA
Cheng
Lan
L
Mericko
Patricia
P
Dickeson
S Kent
SK
Stricker
Thomas P
TP
Santoro
Samuel A
SA
Kahn
Mark L
ML
D000818:Animals; D001773:Blood Cells / Q000166:cytology; D001854:Bone Marrow Cells / Q000166:cytology; D002448:Cell Adhesion; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D039421:Integrin alpha2 / Q000235:genetics / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism; D015471:Leukemia, Basophilic, Acute / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000196:embryology; D008533:Megakaryocytes / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010980:Platelet Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D017354:Point Mutation; D011485:Protein Binding; D011828:Radiation Chimera; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D034061:Thrombopoiesis
D039421:Integrin alpha2; D019012:Integrin beta1; D010980:Platelet Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; C098341:platelet membrane glycoprotein VI; D003094:Collagen