NCAM140 stimulates integrin-dependent cell migration by ectodomain shedding.
The neural cell adhesion molecule (NCAM) plays a key role in neural development, regeneration and synaptic plasticity. This study describes a novel function of NCAM140 in stimulating integrin-dependent cell migration. Expression of NCAM140 in rat B35 neuroblastoma cells resulted in increased migration toward the extracellular matrix proteins fibronectin, collagen IV, vitronectin, and laminin. NCAM-potentiated cell migration toward fibronectin was dependent on beta1 integrins and required extracellular-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) activity. NCAM140 in B35 neuroblastoma cells was subject to ectodomain cleavage resulting in a 115 kDa soluble fragment released into the media and a 30 kDa cytoplasmic domain fragment remaining in the cell membrane. NCAM140 ectodomain cleavage was stimulated by the tyrosine phosphatase inhibitor pervanadate and inhibited by the broad spectrum metalloprotease inhibitor GM6001, characteristic of a metalloprotease. Moreover, treatment of NCAM140-B35 cells with GM6001 reduced NCAM140-stimulated cell migration toward fibronectin and increased cellular attachment to fibronectin to a small but significant extent. These results suggested that metalloprotease-induced cleavage of NCAM140 from the membrane promotes integrin- and ERK1/2-dependent cell migration to extracellular matrix proteins.
Diestel
Simone
S
Department of Biochemistry, Institute of Physiology, Biochemistry and Animal Health, University of Bonn, Bonn, Germany.
Hinkle
C Leann
CL
Schmitz
Brigitte
B
Maness
Patricia F
PF
D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D015816:Cell Adhesion Molecules, Neuronal / Q000502:physiology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D016023:Integrins / Q000502:physiology*; D045726:Metalloproteases / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D051381:Rats; D014162:Transfection; D014638:Vanadates / Q000494:pharmacology
D015816:Cell Adhesion Molecules, Neuronal; D004151:Dipeptides; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D016023:Integrins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; C507071:NCAM140, rat; D011480:Protease Inhibitors; C076715:pervanadate; D014638:Vanadates; D048049:Extracellular Signal-Regulated MAP Kinases; D017027:Protein Tyrosine Phosphatases; D045726:Metalloproteases