title: Collapsin response mediator proteins (CRMPs) are a new class of microtubule-associated protein (MAP) that selectively interacts with assembled microtubules via a taxol-sensitive binding interaction.
abstract: Collapsin response mediator proteins are ubiquitously expressed from multiple genes (CRMPs 1-5) and play important roles in dividing cells and during semaphorin 3A (Sema3A) signaling. Nonetheless, their mode of action remains opaque. Here we carried out in vivo and in vitro assays that demonstrate that CRMPs are a new class of microtubule-associated protein (MAP). In experiments with CRMP1 or CRMP2 and their derivatives, only the C-terminal region (residues 490-572) mediated microtubule binding. The in vivo microtubule association of CRMPs was abolished by taxol or epothilone B, which is highly unusual. CRMP2-depleted cells exhibited destabilized anaphase astral microtubules and altered spindle position. In a cell-based assay, all CRMPs stabilized interphase microtubules against nocodazole-mediated depolymerization, with CRMP1 being the most potent. Remarkably, a 82-residue C-terminal region of CRMP1 or CRMP2, unrelated to other microtubule binding motifs, is sufficient to stabilize microtubules. In cells, we demonstrate that glycogen synthase kinase-3β (GSK3β) inhibition potentiates this activity. Thus, CRMPs are a new class of MAP that binds through a unique motif, but in common with others such as Tau, is antagonized by GSK3β. This regulation is consistent with such kinases being critical for the Sema3A (collapsin) pathway. These findings have implications for cancer and neurodegeneration.
authors.affiliation: Institute of Medical Biology, 8A Biomedical Grove, Singapore 138648.
authors.forename: Pao-Chun
authors.initials: PC
authors.lastname: Lin
authors.affiliation: Small G-protein Signaling and Kinases (sGSK-NRP) Group, Neuroscience Research Partnership, 61 Biopolis Drive, Singapore 138673.
authors.forename: Perry M
authors.initials: PM
authors.lastname: Chan
authors.affiliation: Institute of Neurology, University College London, 1 Wakefield Street, London WC1N 1PJ, United Kingdom.
authors.forename: Christine
authors.initials: C
authors.lastname: Hall
authors.affiliation: Small G-protein Signaling and Kinases (sGSK-NRP) Group, Neuroscience Research Partnership, 61 Biopolis Drive, Singapore 138673; Institute of Medical Biology, 8A Biomedical Grove, Singapore 138648. Electronic address: ed.manser@imb.a-star.edu.sg.
authors.forename: Ed
authors.initials: E
authors.lastname: Manser
mesh_terms: D020816:Amino Acid Motifs; D000705:Anaphase / Q000187:drug effects / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D034261:Epothilones / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051381:Rats; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*; D000098855:Collapsin Response Mediator Protein 1
chemical_list: D034261:Epothilones; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D036341:Intercellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D017239:Paclitaxel; D040121:Semaphorin-3A; D050257:Tubulin Modulators; C502872:Crmp1 protein, mouse; D000098855:Collapsin Response Mediator Protein 1; C488217:Sema3a protein, mouse; C488218:Sema3a protein, rat; C095114:collapsin response mediator protein-2; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; C093788:epothilone B