Generation and nuclear translocation of sumoylated transmembrane fragment of cell adhesion molecule L1.
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Generation and nuclear translocation of sumoylated transmembrane fragment of cell adhesion molecule L1. / Lutz, David; Wolters, Gerrit; Joshi, Gunjan; Djogo, Nevena; Jakovcevski, Igor; Schachner, Melitta; Kleene, Ralf.
in: J BIOL CHEM, Jahrgang 287, Nr. 21, 21, 2012, S. 17161-17175.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Generation and nuclear translocation of sumoylated transmembrane fragment of cell adhesion molecule L1.
AU - Lutz, David
AU - Wolters, Gerrit
AU - Joshi, Gunjan
AU - Djogo, Nevena
AU - Jakovcevski, Igor
AU - Schachner, Melitta
AU - Kleene, Ralf
PY - 2012
Y1 - 2012
N2 - The functions of the cell adhesion molecule L1 in the developing and adult nervous system are triggered by homophilic and heterophilic interactions that stimulate signal transductions that activate cellular responses. Here, we show that stimulation of signaling by function-triggering L1 antibodies or L1-Fc leads to serine protease-dependent cleavage of full-length L1 at the plasma membrane and generation of a sumoylated transmembrane 70-kDa fragment comprising the intracellular and transmembrane domains and part of the extracellular domain. The 70-kDa transmembrane fragment is transported from the plasma membrane to a late endosomal compartment, released from endosomal membranes into the cytoplasm, and transferred from there into the nucleus by a pathway that depends on importin and chromatin-modifying protein 1. Mutation of the sumoylation site at Lys(1172) or of the nuclear localization signal at Lys(1147) abolished L1-stimulated generation or nuclear import of the 70-kDa fragment, respectively. Nuclear import of the 70-kDa fragment may activate cellular responses in parallel or in association with phosphorylation-dependent signaling pathways. Alterations in the levels of the 70-kDa fragment during development and in the adult after spinal cord injury or in a mouse model of Alzheimer disease suggest that this fragment is functionally implicated in development, regeneration, neurodegeneration, tumorigenesis, and possibly synaptic plasticity in the mature nervous system.
AB - The functions of the cell adhesion molecule L1 in the developing and adult nervous system are triggered by homophilic and heterophilic interactions that stimulate signal transductions that activate cellular responses. Here, we show that stimulation of signaling by function-triggering L1 antibodies or L1-Fc leads to serine protease-dependent cleavage of full-length L1 at the plasma membrane and generation of a sumoylated transmembrane 70-kDa fragment comprising the intracellular and transmembrane domains and part of the extracellular domain. The 70-kDa transmembrane fragment is transported from the plasma membrane to a late endosomal compartment, released from endosomal membranes into the cytoplasm, and transferred from there into the nucleus by a pathway that depends on importin and chromatin-modifying protein 1. Mutation of the sumoylation site at Lys(1172) or of the nuclear localization signal at Lys(1147) abolished L1-stimulated generation or nuclear import of the 70-kDa fragment, respectively. Nuclear import of the 70-kDa fragment may activate cellular responses in parallel or in association with phosphorylation-dependent signaling pathways. Alterations in the levels of the 70-kDa fragment during development and in the adult after spinal cord injury or in a mouse model of Alzheimer disease suggest that this fragment is functionally implicated in development, regeneration, neurodegeneration, tumorigenesis, and possibly synaptic plasticity in the mature nervous system.
KW - Animals
KW - Humans
KW - Disease Models, Animal
KW - Mice
KW - Mutation
KW - Protein Structure, Tertiary
KW - HEK293 Cells
KW - Signal Transduction
KW - Nerve Tissue Proteins/metabolism
KW - Neural Cell Adhesion Molecule L1/genetics/metabolism
KW - Active Transport, Cell Nucleus/genetics
KW - Alzheimer Disease/genetics/metabolism
KW - Cell Nucleus/genetics/metabolism
KW - Endosomes/genetics/metabolism
KW - Intracellular Membranes/metabolism
KW - Nuclear Localization Signals/genetics/metabolism
KW - Spinal Cord/embryology/metabolism
KW - Spinal Cord Injuries/genetics/metabolism
KW - Sumoylation
KW - Animals
KW - Humans
KW - Disease Models, Animal
KW - Mice
KW - Mutation
KW - Protein Structure, Tertiary
KW - HEK293 Cells
KW - Signal Transduction
KW - Nerve Tissue Proteins/metabolism
KW - Neural Cell Adhesion Molecule L1/genetics/metabolism
KW - Active Transport, Cell Nucleus/genetics
KW - Alzheimer Disease/genetics/metabolism
KW - Cell Nucleus/genetics/metabolism
KW - Endosomes/genetics/metabolism
KW - Intracellular Membranes/metabolism
KW - Nuclear Localization Signals/genetics/metabolism
KW - Spinal Cord/embryology/metabolism
KW - Spinal Cord Injuries/genetics/metabolism
KW - Sumoylation
M3 - SCORING: Journal article
VL - 287
SP - 17161
EP - 17175
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 21
M1 - 21
ER -
