title: Atypical protein kinase C and Par3 are required for proteoglycan-induced axon growth inhibition.
abstract: When the CNS is injured, damaged axons do not regenerate. This failure is due in part to the growth-inhibitory environment that forms at the injury site. Myelin-associated molecules, repulsive axon guidance molecules, and extracellular matrix molecules including chondroitin sulfate proteoglycans (CSPGs) found within the glial scar inhibit axon regeneration but the intracellular signaling mechanisms triggered by these diverse molecules remain largely unknown. Here we provide biochemical and functional evidence that atypical protein kinase C (PKCζ) and polarity (Par) complex proteins mediate axon growth inhibition. Treatment of postnatal rat neurons in vitro with the NG2 CSPG, a major component of the glial scar, activates PKCζ, and this activation is both necessary and sufficient to inhibit axonal growth. NG2 treatment also activates Cdc42, increases the association of Par6 with PKCζ, and leads to a Par3-dependent activation of Rac1. Transfection of neurons with kinase-dead forms of PKCζ, dominant-negative forms of Cdc42, or mutant forms of Par6 that do not bind to Cdc42 prevent NG2-induced growth inhibition. Similarly, transfection with either a phosphomutant Par3 (S824A) or dominant-negative Rac1 prevent inhibition, whereas expression of constitutively active Rac1 inhibits axon growth on control surfaces. These results suggest a model in which NG2 binding to neurons activates PKCζ and modifies Par complex function. They also identify the Par complex as a novel therapeutic target for promoting axon regeneration after CNS injury.
authors: Department of Neurobiology and Behavior and Program in Neuroscience, Stony Brook University, Stony Brook, New York 11794, USA.
authors: Seong-il
authors: SI
authors: Lee
authors: Weibing
authors: W
authors: Zhang
authors: Mayuri
authors: M
authors: Ravi
authors: Markus
authors: M
authors: Weschenfelder
authors: Martin
authors: M
authors: Bastmeyer
authors: Joel M
authors: JM
authors: Levine
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000941:Antigens / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002645:Chickens; D002921:Cicatrix / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology*; D011509:Proteoglycans / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099216:Chondroitin Sulfate Proteoglycan 4; D000099221:Protein Kinase C zeta
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000941:Antigens; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D011493:Protein Kinase C; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4; D000099221:Protein Kinase C zeta; C115084:Pard3 protein, mouse
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