With a little help from EphA3 and polysialic acid: ectodomain shedding of NCAM is gaining momentum
| العنوان: | With a little help from EphA3 and polysialic acid: ectodomain shedding of NCAM is gaining momentum |
|---|---|
| المؤلفون: | Alexander Dityatev, Herbert Hildebrandt |
| المصدر: | Journal of neurochemistry 128(2), 206-209 (2013). doi:10.1111/jnc.12514 J Neurochem |
| بيانات النشر: | Wiley-Blackwell, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Growth Cones, Biochemistry, Article, Cellular and Molecular Neuroscience, ADAM10 Protein, Adam10 protein, mouse, Animals, Humans, ddc:610, Growth cone, Receptor, Neural Cell Adhesion Molecules, physiology [Growth Cones], biology, Chemistry, Polysialic acid, metabolism [Receptor, EphA3], metabolism [Receptor, EphA5], Receptor, EphA3, Membrane Proteins, Receptor, EphA5, ADAM Proteins, metabolism [Amyloid Precursor Protein Secretases], Cell biology, metabolism [Neural Cell Adhesion Molecules], Membrane protein, Ectodomain, nervous system, metabolism [ADAM Proteins], biology.protein, Neural cell adhesion molecule, Amyloid Precursor Protein Secretases, Amyloid precursor protein secretase, metabolism [Membrane Proteins] |
| الوصف: | EphrinA/EphA-dependent axon repulsion is crucial for synaptic targeting in developing neurons but downstream molecular mechanisms remain obscure. Here, it is shown that ephrinA5/EphA3 triggers proteolysis of the neural cell adhesion molecule (NCAM) by the metalloprotease a disintegrin and metalloprotease (ADAM)10 to promote growth cone collapse in neurons from mouse neocortex. EphrinA5 induced ADAM10 activity to promote ectodomain shedding of polysialic acid-NCAM in cortical neuron cultures, releasing a ~ 250 kDa soluble fragment consisting of most of its extracellular region. NCAM shedding was dependent on ADAM10 and EphA3 kinase activity as shown in HEK293T cells transfected with dominant negative ADAM10 and kinase-inactive EphA3 (K653R) mutants. Purified ADAM10 cleaved NCAM at a sequence within the E-F loop of the second fibronectin type III domain (Leu(671)-Lys(672)/Ser(673)-Leu(674)) identified by mass spectrometry. Mutations of NCAM within the ADAM10 cleavage sequence prevented EphA3-induced shedding of NCAM in HEK293T cells. EphrinA5-induced growth cone collapse was dependent on ADAM10 activity, was inhibited in cortical cultures from NCAM null mice, and was rescued by WT but not ADAM10 cleavage site mutants of NCAM. Regulated proteolysis of NCAM through the ephrin5/EphA3/ADAM10 mechanism likely impacts synapse development, and may lead to excess NCAM shedding when disrupted, as implicated in neurodevelopmental disorders such as schizophrenia. |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::67328d0043fb5375e3312d523491882eTest https://pub.dzne.de/record/137260Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....67328d0043fb5375e3312d523491882e |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |