title: A role for the tyrosine kinase ACK1 in neurotrophin signaling and neuronal extension and branching.
abstract: Neurotrophins are involved in many crucial cellular functions, including neurite outgrowth, synapse formation, and plasticity. Although these events have long been known, the molecular determinants underlying neuritogenesis have not been fully characterized. Ack1 (activated Cdc42-associated tyrosine kinase) is a non-receptor tyrosine kinase that is highly expressed in the brain. Here, we demonstrate that Ack1 is a molecular constituent of neurotrophin signaling cascades in neurons and PC12 cells. We report that Ack1 interacts with Trk receptors and becomes tyrosine phosphorylated and its kinase activity is increased in response to neurotrophins. Moreover, our data indicate that Ack1 acts upstream of the Akt and MAPK pathways. We show that Ack1 overexpression induces neuritic outgrowth and promotes branching in neurotrophin-treated neuronal cells, whereas the expression of Ack1 dominant negatives or short-hairpin RNAs counteract neurotrophin-stimulated differentiation. Our results identify Ack1 as a novel regulator of neurotrophin-mediated events in primary neurons and in PC12 cells.
authors.affiliation: Developmental Neurobiology and Regeneration Lab, IRB Barcelona, Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: La Torre
authors.forename: M
authors.initials: M
authors.lastname: del Mar Masdeu
authors.forename: T
authors.initials: T
authors.lastname: Cotrufo
authors.forename: R S
authors.initials: RS
authors.lastname: Moubarak
authors.forename: J A
authors.initials: JA
authors.lastname: del Río
authors.forename: J X
authors.initials: JX
authors.lastname: Comella
authors.forename: E
authors.initials: E
authors.lastname: Soriano
authors.forename: J M
authors.initials: JM
authors.lastname: Ureña
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020813:Receptor, trkB; C403262:TNK2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3