All in the Family: Primary Megakaryocytes for Studies of Platelet aIIbb3 Signaling
Sanford J. Shattil (1), (2) , Andrew D. Leavitt (3)
Departments of (1) Vascular Biology and (2) Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, (3) Departments of Laboratory Medicine and Internal Medicine, The University of California at San Francisco, San Francisco, C
Summary Integrin aIIbb3 mediates key platelet adhesive responses duringhemostasis and thrombosis. Adhesive ligand binding to aIIbb3 is regulatedby "inside-out" signals, while adhesion-dependent cytoskeletalevents are regulated by "outside-in" signals from aIIbb3. Currently, themolecular basis of bidirectional aIIbb3 signaling is incompletelyunderstood. The functional assessment of integrin signaling pathwaysin nucleated cells has been facilitated by techniques such as viral transductionwhich enable expression of dominant-active and dominantinhibitorygene products. This approach cannot be used with anucleateplatelets. However, recent advances in the ability to expand human andmurine megakaryocytes from hematopoietic stem cells provide a tractableand genetically manipulatable system for studies of aIIbb3 signaling.This overview will discuss some of the advantages and limitationsof this approach and provide examples of its utility. Thus, in addition totheir intrinsic value for understanding hematopoiesis and platelet formation,primary megakaryocytes represent a model system complementaryto platelets for unraveling the remaining mysteries of aIIbb3signaling.