Hyaluronan-CD44 interaction stimulates Rac1 signaling and PKN gamma kinase activation leading to cytoskeleton function and cell migration in astrocytes.
Both hyaluronan [HA, the major glycosaminoglycans in the extracellular matrix (ECM)] and CD44 (a primary HA receptor) are associated with astrocyte activation and tissue repair following central nervous system (CNS) injury. In this study we investigated the question of whether HA-CD44 interaction influences astrocyte signaling and migration. Our data indicated that HA binding to the cultured astrocytes stimulated Rac1 signaling and cytoskeleton-mediated migration. To determine the cellular and molecular basis of these events, we focused on PKN gamma, a Rac1-activated serine/threonine kinase in astrocytes. We determined that HA binding to astrocytes stimulated Rac1-dependent PKN gamma kinase activity which, in turn, up-regulated the phosphorylation of the cytoskeletal protein, cortactin, and attenuated the ability of cortactin to cross-link F-actin. Further analyses indicated that the N-terminal antiparallel coiled-coil (ACC) domains of PKN gamma interacted with Rac1, and transfection of astrocytes with PKN gamma-ACCcDNA inhibited PKN gamma activity. Over-expression of the PKN gamma-ACC domain also functions as a dominant-negative mutant to block HA/CD44-mediated PKN gamma activation of cortactin and astrocyte migration. Taken together, these findings strongly suggest that hyaluronan/CD44 interaction with Rac1-PKN gamma plays a pivotal role in cytoskeleton activation and astrocyte migration. These newly discovered HA/CD44-induced astrocyte function may provide important insight into novel therapeutic treatments for tissue repair following CNS injury.
Bourguignon
Lilly Y W
LY
Department of Medicine, University of California San Francisco, Endocrine Unit (111 N), San Francisco VA Medical Center, San Francisco, CA 94121, USA. lilly.bourguignon@ucsf.edu
Gilad
Eli
E
Peyrollier
Karine
K
Brightman
Amy
A
Swanson
Raymond A
RA
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003599:Cytoskeleton / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection / Q000379:methods; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; C061570:protein kinase N; D011493:Protein Kinase C; D020830:rac1 GTP-Binding Protein