Unc-51-like kinase 1/2-mediated endocytic processes regulate filopodia extension and branching of sensory axons.
The molecular mechanism and significance of endocytic processes involved in directional axon elongation are not well understood. The Unc-51 family of serine/threonine kinases was shown to be important for axon growth and was also linked to endocytosis, providing an entry point to study this problem. We found that mouse Unc-51-like kinase 1/2 (Ulk1/2) proteins are localized to vesicular structures in growth cones of mouse spinal sensory neurons. RNAi-mediated knockdown of Ulk1 and/or Ulk2 resulted in impaired endocytosis of nerve growth factor (NGF), excessive axon arborization, and severely stunted axon elongation. The evidence also indicates that Ulk1/2 mediates a non-clathrin-coated endocytosis in sensory growth cones. Interestingly, NGF can induce the interaction of Ulk1 with TrkA receptor complexes through promoting K63-polyubiquitination of Ulk1 and binding of Ulk1 to the scaffolding protein p62. These results and additional studies suggest that Ulk1/2 proteins regulate filopodia extension and neurite branching during sensory axon outgrowth, probably through regulating TrkA receptor trafficking and signaling.
Zhou
Xiang
X
Department of Cell Biology, Duke University Medical School, Durham, NC 27710, USA.
Babu
J Ramesh
JR
da Silva
Susana
S
Shu
Qing
Q
Graef
Isabella A
IA
Oliver
Tim
T
Tomoda
Toshifumi
T
Tani
Tomomi
T
Wooten
Marie W
MW
Wang
Fan
F
D000818:Animals; D000071189:Autophagy-Related Protein-1 Homolog; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D004622:Embryo, Mammalian; D004705:Endocytosis; D019085:Fluorescent Antibody Technique, Direct; D005727:Ganglia, Spinal / Q000166:cytology / Q000201:enzymology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D020439:Growth Cones / Q000201:enzymology / Q000502:physiology; D006801:Humans; D051379:Mice; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000502:physiology; D009475:Neurons, Afferent / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011554:Pseudopodia / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000187:drug effects; D020917:Receptor, trkA / Q000378:metabolism; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
C490981:Gtf2h1 protein, mouse; D034741:RNA, Small Interfering; D014157:Transcription Factors; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D051758:Transcription Factor TFIIH; D020932:Nerve Growth Factor; C401061:Ulk2 protein, mouse; D020917:Receptor, trkA; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C112444:Ulk1 protein, mouse