title: Activated leukocyte cell adhesion molecule modulates neurotrophin signaling.
abstract: Cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) have been shown to modulate growth factor signaling and follow complex trafficking pathways in neurons. Similarly, several growth factors, including members of the neurotrophin family, undergo axonal retrograde transport that is required to elicit their full signaling potential in neurons. We sought to determine whether IgCAMs that enter the axonal retrograde transport route co-operate with neurotrophin signaling. We identified activated leukocyte cell adhesion molecule (ALCAM), a protein involved in axon pathfinding and development of the neuromuscular junction, to be associated with an axonal endocytic compartment that contains neurotrophins and their receptors. Although ALCAM enters carriers that are transported bidirectionally in motor neuron axons, it is predominantly co-transported with the neurotrophin receptor p75(NTR) toward the cell body. ALCAM was found to specifically potentiate nerve growth factor (NGF)-induced differentiation and signaling. The extracellular domain of ALCAM is both necessary and sufficient to potentiate NGF-induced neurite outgrowth, and its homodimerization is required for this novel role. Our findings indicate that ALCAM synergizes with NGF to induce neuronal differentiation, raising the possibility that it functions not only as an adhesion molecule but also in the modulation of growth factor signaling in the nervous system.
authors.affiliation: Molecular NeuroPathobiology Laboratory, Cancer Research UK London Research Institute, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Wade
authors.forename: Claire
authors.initials: C
authors.lastname: Thomas
authors.forename: Bernadett
authors.initials: B
authors.lastname: Kalmar
authors.forename: Marco
authors.initials: M
authors.lastname: Terenzio
authors.forename: Jerome
authors.initials: J
authors.lastname: Garin
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
authors.forename: Giampietro
authors.initials: G
authors.lastname: Schiavo
mesh_terms: D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D001369:Axons / Q000378:metabolism; D015153:Blotting, Western; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D011992:Endosomes / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D013058:Mass Spectrometry; D008968:Molecular Conformation; D009046:Motor Neurons / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology / Q000502:physiology*; D016501:Neurites / Q000502:physiology; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D020410:Activated-Leukocyte Cell Adhesion Molecule; D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA