The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells

HMG1 (high mobility group I) is a ubiquitous and abundant chromatin compone nt. However, HMG1 can be secreted by activated macrophages and monocytes, a nd can act as a mediator of inflammation and endotoxic lethality. Here we d ocument a role of extracellular HMG1 in cell migration. HMG1 (and its indiv idual DNA-binding domains) stimulated migration of rat smooth muscle cells in chemotaxis, chemokinesis, and wound healing assays. HMG1 induced rapid a nd transient changes of cell shape, and actin cytoskeleton reorganization l eading to an elongated polarized morphology typical of motile cells. These effects were inhibited by antibodies directed against the receptor of advan ced glycation endproducts, indicating that the receptor of advanced glycati on endproducts is the receptor mediating the HMG1-dependent migratory respo nses. Pertussis toxin and the mitogen-activated protein kinase kinase inhib itor PD98059 also blocked HMG1-induced rat smooth muscle cell migration. su ggesting that a G(i/o) protein and mitogen-activated protein kinases are re quired for the HMG1 signaling pathway. We also show that HMG1 can be releas ed by damage or necrosis of a variety of cell types, including endothelial cells. Thus, HMG1 has all the hallmarks of a molecule that can promote athe rosclerosis and restenosis after vascular damage.