title: Kidins220/ARMS mediates the integration of the neurotrophin and VEGF pathways in the vascular and nervous systems.
abstract: Signaling downstream of receptor tyrosine kinases controls cell differentiation and survival. How signals from different receptors are integrated is, however, still poorly understood. In this work, we have identified Kidins220 (Kinase D interacting substrate of 220 kDa)/ARMS (Ankyrin repeat-rich membrane spanning) as a main player in the modulation of neurotrophin and vascular endothelial growth factor (VEGF) signaling in vivo, and a primary determinant for neuronal and cardiovascular development. Kidins220(-/-) embryos die at late stages of gestation, and show extensive cell death in the central and peripheral nervous systems. Primary neurons from Kidins220(-/-) mice exhibit reduced responsiveness to brain-derived neurotrophic factor, in terms of activation of mitogen-activated protein kinase signaling, neurite outgrowth and potentiation of excitatory postsynaptic currents. In addition, mice lacking Kidins220 display striking cardiovascular abnormalities, possibly due to impaired VEGF signaling. In support of this hypothesis, we demonstrate that Kidins220 constitutively interacts with VEGFR2. These findings, together with the data presented in the accompanying paper, indicate that Kidins220 mediates the integration of several growth factor receptor pathways during development, and mediates the activation of distinct downstream cascades according to the location and timing of stimulation.
authors: Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, via Morego 30, 16163 Genoa, Italy. fabrizia.cesca@iit.it
authors: F
authors: F
authors: Cesca
authors: A
authors: A
authors: Yabe
authors: B
authors: B
authors: Spencer-Dene
authors: J
authors: J
authors: Scholz-Starke
authors: L
authors: L
authors: Medrihan
authors: C H
authors: CH
authors: Maden
authors: H
authors: H
authors: Gerhardt
authors: I R
authors: IR
authors: Orriss
authors: P
authors: P
authors: Baldelli
authors: M
authors: M
authors: Al-Qatari
authors: M
authors: M
authors: Koltzenburg
authors: R H
authors: RH
authors: Adams
authors: F
authors: F
authors: Benfenati
authors: G
authors: G
authors: Schiavo
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D009420:Nervous System / Q000187:drug effects / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C544017:Kidins220 protein, mouse; D008565:Membrane Proteins; D009414:Nerve Growth Factors; D042461:Vascular Endothelial Growth Factor A; D053148:Caspase 3