CRMP-2 binds to tubulin heterodimers to promote microtubule assembly

Fukata, Yuko; Itoh, Tomohiko J.; Kimura, Toshihide; Ménager, Céline; Nishimura, Takashi; Shiromizu, Takashi; Watanabe, Hiroyasu; Inagaki, Naoyuki; Iwamatsu, Akihiro; Hotani, Hirokazu; Kaibuchi, Kozo

doi:10.1038/ncb825

Cited by 684 publications

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“…E/ANTH Domains Stimulate Neurite Outgrowth-It was suggested recently that the tubulin-binding protein collapsin response mediator protein-2 stimulates neurite outgrowth in PC12 cells in conjunction with low doses of nerve growth factor, by drawing together tubulin heterodimers beyond a critical concentration required for polymerization (45,46). This is consistent with the observation that PC12 cells require tubulin polymerization and reorganization of the microtubule cytoskeleton for neurite outgrowth to occur (47)(48)(49)(50)(51).…”

Section: Fig 5 Saturation Binding Analysis Of Enth Domain/tubulin Isupporting

confidence: 77%

A Role for Epsin N-terminal Homology/AP180 N-terminal Homology (ENTH/ANTH) Domains in Tubulin Binding

Hussain

Yamabhai

Bhakar

et al. 2003

Journal of Biological Chemistry

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The epsin N-terminal homology (ENTH) domain is a protein module of ϳ150 amino acids found at the N terminus of a variety of proteins identified in yeast, plants, nematode, frog, and mammals. ENTH domains comprise multiple ␣-helices folded upon each other to form a compact globular structure that has been implicated in interactions with lipids and proteins. In characterizing this evolutionarily conserved domain, we isolated and identified tubulin as an ENTH domain-binding partner. The interaction, which is direct and has a dissociation constant of ϳ1 M, was observed with ENTH domains of proteins present in various species. Tubulin is co-immunoprecipitated from rat brain extracts with the ENTH domain-containing proteins, epsins 1 and 2, and punctate epsin staining is observed along the microtubule cytoskeleton of dissociated cortical neurons. Consistent with a role in microtubule processes, the over-expression of epsin ENTH domain in PC12 cells stimulates neurite outgrowth. These data demonstrate an evolutionarily conserved property of ENTH domains to interact with tubulin and microtubules.The epsin N-terminal homology (ENTH) 1 domain is an evolutionarily conserved globular module of ϳ150 amino acids that occurs at the amino terminus of a variety of proteins (1, 2).Originally noted in the plant protein, Af10 (3), the ENTH domain has subsequently been characterized in epsins (2) and enthoprotin (4) (also termed epsinR (5, 6) or Clint (7)), and in yeast proteins including Ent1p/Ent2p (8, 9) and Ent3p (10). Adaptor protein 180 (AP180), clathrin assembly lymphoid myeloid leukemia protein (CALM), Huntingtin-interacting protein-1 (HIP1) and HIP12, and the yeast proteins yAP180 and Sla2p contain a module that is so similar in structure to the epsin ENTH domain that they were initially denoted ENTHbearing proteins (11-13). However, recent structural studies have refined our understanding such that ENTH-like domains from these proteins have been re-designated ANTH domaincontaining proteins in accordance with their higher structural similarity to AP180 rather than epsin (14). In an effort to simplify the nomenclature applied in this study, we refer to these homologous structures as E/ANTH domains when collectively discussing proteins bearing either domain, but maintain the ENTH or ANTH nomenclature when discussing individual proteins.A common feature among many E/ANTH domain-bearing proteins is that their C termini contain peptide motifs, indicative of a functional role in clathrin-mediated membrane budding including clathrin and clathrin adaptor protein-binding elements (1,15). In addition to their interactions with multiple endocytic components, many of the currently characterized E/ANTH proteins, including epsin, AP180, and HIP1/12, are localized to clathrin-coated pits where they function in clathrin-mediated endocytosis (2, 16 -25). Interestingly, enthoprotin is unique in this group because it is predominantly localized to the trans-Golgi network rather than the plasma membrane, and it appears to regulate clathrin-medi...

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Section: Fig 5 Saturation Binding Analysis Of Enth Domain/tubulin Isupporting

confidence: 77%

A Role for Epsin N-terminal Homology/AP180 N-terminal Homology (ENTH/ANTH) Domains in Tubulin Binding

Hussain

Yamabhai

Bhakar

et al. 2003

Journal of Biological Chemistry

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“…There may be significant redundancy in MAPs, as double knockouts of MAP2 and MAP1b and of tau and MAP1b appear to amplify these effects on dendrites and axons, respectively (DiTella et al 1996;Takei et al 2000;Teng et al 2001). Another axonal MAP named collapsin response mediator protein-2 (CRMP-2) binds tubulin dimers and stimulates axon growth and branching in hippocampal neurons in culture (Fukata et al 2002). Finally, microtubule motors such as dynein actively transport microtubules along the length of the axon, are required for axon growth, and may contribute to the microtubule invasion of growth cones during elongation (Ahmad et al 1998).…”

Section: The Growth Cone: Motor and Clutch Of Axon Growthmentioning

confidence: 99%

How does an axon grow?

Goldberg¹

2003

Genes Dev.

203

138

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How do axons grow during development, and why do they fail to regrow when injured? In the complicated mesh of our nervous system, the axon is the information superhighway, carrying all of the data we use to sense our environment and carry out behaviors. To wire up our nervous system properly, neurons must elongate their axons during development to reach their targets. This is no simple task, however. The complex morphology of axons and dendrites puts neurons among the most intricate and beautiful cells in the body. Knowledge of how neurons extend axons and dendrites, elongate at a particular rate, and stop growing at the proper time is critical to understanding the development of our nervous system, yet the regulation of these processes is poorly understood. Considerable attention in recent years has focused on understanding how growth cones are guided and steered through complicated pathways (for review, see Schmidt and Hall 1998;Mueller 1999), and even how neurons initiate new processes (for review, see Da Silva and Dotti 2002), but what mechanisms are involved in elongation itself? Are environmental signals needed to drive axon growth and, if so, what are the intracellular molecular mechanisms by which they induce elongation? What controls the rate of axon growth? How do CNS neurons know whether to extend axons or dendrites? Is the signaling of axon versus dendrite growth attributable to different extracellular signals, different neuronal states, or both? All of these questions bear critically on our understanding of axon growth and here I review recent answers and approaches to the above questions, and highlight their relevance during development, injury, and disease.

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“…Ulip1 (TUC4͞CRMP͞UNC-33͞Dpysl3) is a neuroD2-regulated gene identified in unpublished microarray studies in our laboratory. Ulip1protein is involved in synapse structural remodeling by promoting microtubule assembly and in neurite outgrowth during embryogenesis (15)(16)(17). Synaptic remodeling also occurs during consolidation of emotional memory in lateral amygdala (17); therefore, we asked whether Ulip1 expression was altered in neuroD2 mutant mice.…”

Section: Ulip1 Is Reduced In Neurod2-deficient Mice and Is A Direct Nmentioning

confidence: 99%

“…During consolidation, the cAMP response element-binding protein is activated by kinases such as protein kinase A and mitogen-associated protein kinase resulting in transcriptional activation of genes that contribute to synaptic remodeling. Cytoskeletal proteins, such as Ulip family members, have been implicated in structural changes associated with synaptic strengthening (15)(16)(17). During the association of the conditioned and unconditioned stimuli, the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is synthesized and inserted into active synapses, a possible mechanism for strengthening glutamatergic signaling in the postsynaptic neuron.…”

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confidence: 99%

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

Lin

Hansen

Wang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The amygdala is centrally involved in formation of emotional memory and response to fear or risk. We have demonstrated that the lateral and basolateral amygdala nuclei fail to form in neuroD2 null mice and neuroD2 heterozygotes have fewer neurons in this region. NeuroD2 heterozygous mice show profound deficits in emotional learning as assessed by fear conditioning. Unconditioned fear was also diminished in neuroD2 heterozygotes compared to wild-type controls. Several key molecular regulators of emotional learning were diminished in the brains of neuroD2 heterozygotes including Ulip1, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, and GABA A receptor. Thus, neuroD2 is essential for amygdala development and genes involved in amygdala function are altered in neuroD2-deficient mice.basic helix-loop-helix ͉ haploinsufficiency T he amygdala is an almond-shaped brain structure that integrates emotional learning and other emotional responses such as fear perception. The role of the amygdala in fear perception and response was established through lesioning studies in animals and confirmed through positron emission tomography and functional magnetic resonance imaging in normal human subjects and in schizophrenic patients with deficits in fear processing (1-9).We previously reported that neuroD2-null mice on a mixed genetic background are indistinguishable from littermates at birth, but fail to thrive and die within weeks of birth. Before death, nullizygous mice develop ataxia, seizures, cerebellar degeneration, and growth retardation. NeuroD2 heterozygotes appear normal as adults, but have reduced seizure threshold and mild ataxia. We observed aggressive behavior between neuroD2 heterozygotes, which prompted us to evaluate the function and structure of the amygdala and related limbic system brain regions that control aggression, fear, and other emotions. Unconditioned fear (also referred to as anxiety or risk perception) is the response to environmental cues that signal danger. The basolateral amygdala and ventral subiculum of hippocampus are involved in unconditioned fear responses; however, the neuronal circuitry and molecular mechanisms are poorly understood (10).In contrast to unconditioned fear, the neurochemical and molecular basis of emotional learning related to conditioned fear are being elucidated through studies that evaluate fear conditioning in the context of pharmacologic or genetic manipulation of neurotransmitter receptors and second messengers. Fear conditioning involves coupling a neutral conditioned stimulus (CS) such as an audible tone with a noxious unconditioned stimulus (US) such as foot shock and observing that after training and rest periods, that the CS alone is sufficient to elicit behavioral (e.g., freezing) and autonomic responses (11,12). During the training and rest period, the lateral amygdala acquires and consolidates short-and long-term memory that associates the conditioned and unconditioned stimuli through a process known as emotional learning.The acquisition phas...

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CRMP-2 binds to tubulin heterodimers to promote microtubule assembly

Cited by 684 publications

References 43 publications

A Role for Epsin N-terminal Homology/AP180 N-terminal Homology (ENTH/ANTH) Domains in Tubulin Binding

A Role for Epsin N-terminal Homology/AP180 N-terminal Homology (ENTH/ANTH) Domains in Tubulin Binding

How does an axon grow?

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

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