The ubiquitin ligase Rnf6 regulates local LIM kinase 1 levels in axonal growth cones.
LIM kinase 1 (LIMK1) controls important cellular functions such as morphogenesis, cell motility, tumor cell metastasis, development of neuronal projections, and growth cone actin dynamics. We have investigated the role of the RING finger protein Rnf6 during neuronal development and detected high Rnf6 protein levels in developing axonal projections of motor and DRG neurons during mouse embryogenesis as well as cultured hippocampal neurons. RNAi-mediated knock-down experiments in primary hippocampal neurons identified Rnf6 as a regulator of axon outgrowth. Consistent with a role in axonal growth, we found that Rnf6 binds to, polyubiquitinates, and targets LIMK1 for proteasomal degradation in growth cones of primary hippocampal neurons. Rnf6 is functionally linked to LIMK1 during the development of axons, as the changes in axon outgrowth induced by up- or down-regulation of Rnf6 levels can be restored by modulation of LIMK1 expression. Thus, these results assign a specific role for Rnf6 in the control of cellular LIMK1 concentrations and indicate a new function for the ubiquitin/proteasome system in regulating local growth cone actin dynamics.
Tursun
Baris
B
Zentrum für Molekulare Neurobiologie Hamburg, Universität Hamburg, 20251 Hamburg, Germany.
Schlüter
Anne
A
Peters
Marvin A
MA
Viehweger
Birte
B
Ostendorff
Heather P
HP
Soosairajah
Juliana
J
Drung
Alexander
A
Bossenz
Michael
M
Johnsen
Steven A
SA
Schweizer
Michaela
M
Bernard
Ora
O
Bach
Ingolf
I
D000199:Actins / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D020439:Growth Cones / Q000201:enzymology*; D006624:Hippocampus / Q000166:cytology / Q000196:embryology*; D006801:Humans; D054461:Lim Kinases; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
D000199:Actins; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; C119753:RNF6 protein, human; D025801:Ubiquitin; D011494:Protein Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases; C515893:Limk1 protein, mouse; D046988:Proteasome Endopeptidase Complex