PECAMigration

Generation of platelets from their megakaryocyte precursors is a multistep process involving differentiation and migration of maturing megakaryocytes within the bone marrow compartment, formation of proplatelets, and release of young platelets into the bloodstream. New work from Dhanjal and colleagues describes an unsuspected role for the cell adhesion and signaling molecule, PECAM-1, in this process.

PECAM-1 is a 130-kDa transmembrane glycoprotein that is expressed prominently at endothelial cell-cell junctions, on many leukocyte subsets, and on the surface of platelets and megakaryocytes. The most amino terminal of PECAM-1's 6 immunoglobulin homology domains has homophilic binding properties, while the rather complex cytoplasmic domain contains, among other features, 2 immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that become phosphorylated upon cellular activation, creating docking sites on the inner face of the plasma membrane for a number of well-characterized cytosolic signaling molecules, the best characterized being the SH2 domain–containing protein-tyrosine phosphatase, SHP-2.

Many cytoskeletal elements and cell surface adhesion and signaling molecules are involved in cell migration, and there are numerous observations that suggest that PECAM-1 plays a positive role in this process. Because of its expression at endothelial cell junctions, PECAM-1 has long been suspected of being a participant in endothelial-cell migration, and a multitude of in vitro and in vivo studies have demonstrated that PECAM-1 enhances the rate and/or efficiency of directed endothelial-cell migration during angiogenesis and wound healing. Thus, endothelial cells derived from PECAM-1–deficient mice were found to exhibit reduced migration rates in vitro,¹  and form new blood vessels at a slower rate in vivo,²  as do human umbilical vein endothelial cells (HUVECs) treated with PECAM-1–specific antisense oligonucleotides.¹  The mechanism by which PECAM-1 promotes cell migration appears to depend on the nature of the external stimulus encountered by the cell, as some reports have implicated ITIM-dependent formation of PECAM-1/SHP-2 signaling complexes in the process,^3,4  while another¹  found that ITIM-independent, PECAM-1–mediated regulation of the small GTPase, Rho, played the more important role. No matter what the operative mechanism, however, these data collectively provide strong support for the notion that PECAM-1 adhesion and/or signaling contribute importantly to spatially directed endothelial-cell migration.

In the present article, Dhanjal and colleagues extend these observations by uncovering a role for PECAM-1 in the coordinated migration of megakaryocytes—a critical component of the process of thrombopoiesis. They found, similar to the situation in endothelial cells, that PECAM-1–deficient megakaryocytes fail to properly regulate directional migration—a process in megakaryocytes that is initiated by the binding of the chemokine, SDF1, to its 7-transmembrane, G protein–coupled receptor (GPCR), CXCR4. As a consequence, the efficiency with which megakaryocytes migrate from the so-called osteoblastic niche within the bone marrow to the capillary-rich vascular niche, where they make contact with sinusoidal endothelial cells, produce proplatelets, and release them into the blood stream, is markedly reduced.

What is the mechanism by which PECAM-1 contributes to directional migration of megakaryocytes? One hint comes from the observation by the authors that PECAM-1–deficient megakaryocytes fail to translocate CXCR4, remodel actin, and form lamellopodia at the leading edge of the cell. Failure to properly polarize this GPCR is somewhat reminiscent of the observations of Gratzinger and colleagues,¹  in which PECAM-1–deficient endothelial cells failed to target the GPCRs, EDG1 and EDG3, to membrane rafts, thus affecting the coordinated activation of Rho, which in turn modulates the dynamics of actin cytoskeleton and focal adhesions—both of which play an important role in directed pseudopod extension and productive cell migration. How PECAM-1 might influence the membranous distribution of any of these GPCRs is not known. It is also possible, however, that PECAM-1 functions to regulate directional cell migration simply by controlling the subcellular distribution of its binding partner, SHP-2, which via its phosphatase activity promotes assembly/disassembly of structural proteins that comprise focal adhesion complexes.⁵  Because the efficiency of directional megakaryocyte migration influences (1) the time to recovery of normal platelet counts following radiation therapy or chemotherapy, and (2) the dynamics of platelet production in patients suffering from any of the immune thrombocytopenias, further studies such as the one by Dhanjal et al aimed at advancing our understanding of the role of PECAM-1 in the migration of the blood and vascular cells in which it is expressed should be of considerable interest and importance.