title: A Sonic hedgehog coreceptor, BOC regulates neuronal differentiation and neurite outgrowth via interaction with ABL and JNK activation.
abstract: Neurite outgrowth is a critical step for neurogenesis and remodeling synaptic circuitry during neuronal development and regeneration. An immunoglobulin superfamily member, BOC functions as Sonic hedgehog (Shh) coreceptor in canonical and noncanonical Shh signaling in neuronal development and axon outgrowth/guidance. However signaling mechanisms responsible for BOC action during these processes remain unknown. In our previous studies, a multiprotein complex containing BOC and a closely related protein CDO promotes myogenic differentiation through activation of multiple signaling pathways, including non-receptor tyrosine kinase ABL. Given that ABL and Jun. N-terminal kinase (JNK) are implicated in actin cytoskeletal dynamics required for neurogenesis, we investigated the relationship between BOC, ABL and JNK during neuronal differentiation. Here, we demonstrate that BOC and ABL are induced in P19 embryonal carcinoma (EC) cells and cortical neural progenitor cells (NPCs) during neuronal differentiation. BOC-depleted EC cells or Boc-/-NPCs exhibit impaired neuronal differentiation with shorter neurite formation. BOC interacts with ABL through its putative SH2 binding domain and seems to be phosphorylated in an ABL activity-dependent manner. Unlike wildtype BOC, ABL-binding defective BOC mutants exhibit impaired JNK activation and neuronal differentiation. Finally, Shh treatment enhances JNK activation which is diminished by BOC depletion. These data suggest that BOC interacts with ABL and activates JNK thereby promoting neuronal differentiation and neurite outgrowth.
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, Republic of Korea.
authors.forename: Tuan Anh
authors.initials: TA
authors.lastname: Vuong
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, Republic of Korea.
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Leem
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, Republic of Korea.
authors.forename: Bok-Geon
authors.initials: BG
authors.lastname: Kim
authors.affiliation: Department of Physiology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, Republic of Korea.
authors.forename: Hana
authors.initials: H
authors.lastname: Cho
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.
authors.forename: Gyu-Un
authors.initials: GU
authors.lastname: Bae
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, Republic of Korea. Electronic address: kangj01@skku.edu.
authors.forename: Jong-Sun
authors.initials: JS
authors.lastname: Kang
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002454:Cell Differentiation; D004789:Enzyme Activation; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D000071446:Neuronal Outgrowth; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: C474334:BOC protein, human; C510745:Boc protein, mouse; D053823:Hedgehog Proteins; D007074:Immunoglobulin G; D011956:Receptors, Cell Surface; D019000:Phosphotyrosine; D016315:Proto-Oncogene Proteins c-abl; D048031:JNK Mitogen-Activated Protein Kinases
keywords: ABL; BOC; JNK; Neurite outgrowth; Neuronal differentiation; Shh coreceptor