Sustained activation of N-WASP through phosphorylation is essential for neurite extension.
Neurite extension is a key process for constructing neuronal circuits during development and remodeling of the nervous system. Here we show that Src family tyrosine kinases and proteasome degradation signals synergistically regulate N-WASP in neurite extension. Src family kinases activate N-WASP through tyrosine phosphorylation, which induces Arp2/3 complex-mediated actin polymerization. Tyrosine phosphorylation of N-WASP also initiates its degradation through ubiquitination. When neurite growth is stimulated in culture, degradation of N-WASP is markedly inhibited, leading to accumulation of the phosphorylated N-WASP. On the other hand, under culture conditions that inhibit neurite extension, but favor proliferation, the phosphorylated N-WASP is degraded rapidly. Collectively, neurite extension is regulated by the balance of N-WASP phosphorylation (activation) and degradation (inactivation), which are induced by tyrosine phosphorylation.
Suetsugu
Shiro
S
Department of Biochemistry, 4-6-1 Shirokanedai, Minato-ku, 108-8639, Tokyo, Japan.
Hattori
Mitsuharu
M
Miki
Hiroaki
H
Tezuka
Tohru
T
Yamamoto
Tadashi
T
Mikoshiba
Katsuhiko
K
Takenawa
Tadaomi
T
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051377:Actin-Related Protein 2; D051378:Actin-Related Protein 3; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000502:physiology*; D016716:PC12 Cells; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D051381:Rats; D018411:Spodoptera; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D051377:Actin-Related Protein 2; D051378:Actin-Related Protein 3; C495927:Actr2 protein, mouse; C495929:Actr3 protein, mouse; D015853:Cysteine Proteinase Inhibitors; D003598:Cytoskeletal Proteins; D007976:Leupeptins; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; C495772:Wasl protein, mouse; C495770:Wasl protein, rat; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; C067713:lactacystin; C494960:Fyn protein, mouse; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D020764:cdc42 GTP-Binding Protein; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine