title: Rabin8 regulates neurite outgrowth in both GEF activity-dependent and -independent manners.
abstract: Many aspects of membrane-trafficking events are regulated by Rab-family small GTPases. Neurite outgrowth requires massive addition of proteins and lipids to the tips of growing neurites by membrane trafficking, and although several Rabs, including Rab8, Rab10, and Rab11, have been implicated in this process, their regulatory mechanisms during neurite outgrowth are poorly understood. Here, we show that Rabin8, a Rab8-guanine nucleotide exchange factor (GEF), regulates nerve growth factor (NGF)-induced neurite outgrowth of PC12 cells. Knockdown of Rabin8 results in inhibition of neurite outgrowth, whereas overexpression promotes it. We also find that Rab10 is a novel substrate of Rabin8 and that both Rab8 and Rab10 function during neurite outgrowth downstream of Rabin8. Surprisingly, however, a GEF activity-deficient isoform of Rabin8 also promotes neurite outgrowth, indicating the existence of a GEF activity-independent role of Rabin8. The Arf6/Rab8-positive recycling endosomes (Arf6/Rab8-REs) and Rab10/Rab11-positive REs (Rab10/Rab11-REs) in NGF-stimulated PC12 cells are differently distributed. Rabin8 localizes on both RE populations and appears to activate Rab8 and Rab10 there. These localizations and functions of Rabin8 are Rab11 dependent. Thus Rabin8 regulates neurite outgrowth both by coordinating with Rab8, Rab10, and Rab11 and by a GEF activity-independent mechanism.
authors.affiliation: Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Homma
authors.affiliation: Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai, Miyagi 980-8578, Japan nori@m.tohoku.ac.jp.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D000081410:Germinal Center Kinases; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D016501:Neurites / Q000378:metabolism; D000071446:Neuronal Outgrowth; D016716:PC12 Cells; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D004268:DNA-Binding Proteins; D000081410:Germinal Center Kinases; D020662:Guanine Nucleotide Exchange Factors; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C528734:GLUT4 enhancer factor, mouse; C520736:Rab10 protein, mouse