Specific and redundant roles of Src and Fyn in organizing the cytoskeleton.
Mouse embryos lacking Csk, a negative regulator of Src family kinases, exhibit defects in neurulation and die at mid-gestation. To determine the role of activated Src family kinases in the csk- phenotype, we have introduced mutations in the src and fyn genes into the csk- mutant background. Genetic analysis reveals that src, but not fyn, is partly epistatic to the csk gene. Biochemical analysis indicates that several cytoskeletal proteins are hyperphosphorylated on tyrosine residues in csk- cells. Regulation of cortactin and tensin hyperphosphorylation is Src-dependent, whereas focal adhesion kinase and paxillin hyperphosphorylation is partly dependent on both Src and Fyn. Furthermore, the src- mutation can restore the normal distribution of cortactin and partly correct filamentous actin organization in csk-cells. Thus, Src family kinases have both specific and overlapping functions in regulation of the cytoskeleton. The disturbance of these functions may be a molecular basis for the phenotype exhibited by csk- mutants.
Thomas
S M
SM
Division of Molecular Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA.
Soriano
P
P
Imamoto
A
A
D000818:Animals; D001483:Base Sequence; D000081247:CSK Tyrosine-Protein Kinase; D015815:Cell Adhesion Molecules / Q000502:physiology; D002460:Cell Line; D003599:Cytoskeleton / Q000502:physiology*; D017931:DNA Primers; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology; D004789:Enzyme Activation; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010641:Phenotype; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051076:Proto-Oncogene Proteins c-fyn; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases
D015815:Cell Adhesion Molecules; D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases