Focal adhesion kinase in the brain: novel subcellular localization and specific regulation by Fyn tyrosine kinase in mutant mice.
Signaling by tyrosine kinases is required for the induction of synaptic plasticity in the central nervous system. Comparison of fyn, src, yes, and abl nonreceptor tyrosine kinase mutant mice shows a specific requirement for Fyn in the induction of long-term potentiation at CA1 synapses in the hippocampus. To identify components of a Fyn-dependent pathway that may be involved with hippocampus function we examined tyrosine-phosphorylated proteins in kinase mutant mice. We found that nine proteins were hypophosphorylated specifically in fyn mutants. One of the hypophosphorylated proteins was focal adhesion tyrosine kinase (FAK). FAK also showed reduced activity in immunocomplex kinase assays only in fyn mutants. FAK is expressed at very high levels in the brain but in contrast to non-neural cells, FAK was not restricted to focal adhesion contacts. FAK was found in axons, dendrites, and the intermediate filament cytoskeleton of astrocytes. Brain extracts from the mutants also show specific patterns of compensatory changes in the activity of the remaining Src family kinases. Tyrosine phosphorylation is a critical regulator of FAK, and impairments in FAK signal transduction in fyn mutants may contribute to the mutant neural phenotype.
Grant
S G
SG
Center for Genome Research, University of Edinburgh, UK.
Karl
K A
KA
Kiebler
M A
MA
Kandel
E R
ER
D000818:Animals; D001253:Astrocytes / Q000201:enzymology; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000302:isolation & purification / Q000378:metabolism*; D002451:Cell Compartmentation; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015971:Gene Expression Regulation, Enzymologic; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000201:enzymology; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000302:isolation & purification / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D051575:Proto-Oncogene Proteins c-yes; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000502:physiology; D014018:Tissue Distribution; D019061:src-Family Kinases
D015815:Cell Adhesion Molecules; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D051575:Proto-Oncogene Proteins c-yes; D016392:Proto-Oncogene Proteins pp60(c-src); C496051:Ptk2 protein, mouse; C496639:Yes1 protein, mouse; D019061:src-Family Kinases