Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development.
Nedd4-1 is a "neuronal precursor cell expressed and developmentally downregulated protein" and among the most abundant E3 ubiquitin ligases in mammalian neurons. In analyses of conventional and conditional Nedd4-1-deficient mice, we found that Nedd4-1 plays a critical role in dendrite formation. Nedd4-1, the serine/threonine kinase TNIK, and Rap2A form a complex that controls Nedd4-1-mediated ubiquitination of Rap2A. Ubiquitination by Nedd4-1 inhibits Rap2A function, which reduces the activity of Rap2 effector kinases of the TNIK family and promotes dendrite growth. We conclude that a Nedd4-1/Rap2A/TNIK signaling pathway regulates neurite growth and arborization in mammalian neurons.
Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany. kawabe@em.mp.de
Hiroshi
H
Kawabe
Antje
A
Neeb
Kalina
K
Dimova
Samuel M
SM
Young
Michiko
M
Takeda
Shutaro
S
Katsurabayashi
Miso
M
Mitkovski
Oxana A
OA
Malakhova
Dong-Er
DE
Zhang
Masato
M
Umikawa
Ken-ichi
K
Kariya
Sandra
S
Goebbels
Klaus-Armin
KA
Nave
Christian
C
Rosenmund
Olaf
O
Jahn
JeongSeop
J
Rhee
Nils
N
Brose
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D056827:Endosomal Sorting Complexes Required for Transport / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D000081410:Germinal Center Kinases; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus; D006801:Humans; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D000075702:Nedd4 Ubiquitin Protein Ligases; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D016622:Silver Staining / Q000379:methods; D013347:Subcellular Fractions / Q000378:metabolism / Q000648:ultrastructure; D014162:Transfection / Q000379:methods; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020668:rap GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D056827:Endosomal Sorting Complexes Required for Transport; D000081410:Germinal Center Kinases; D018991:Myelin Proteolipid Protein; C047516:Plp1 protein, mouse; D034741:RNA, Small Interfering; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618484:Nedd4 protein, rat; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; C000631454:TNIK protein, human; C116756:RAP2A protein, human; D020668:rap GTP-Binding Proteins