Mutation of a phenylalanine conserved in SH3-containing tyrosine kinases activates the transforming ability of c-Abl.
c-abl is the normal cellular homolog of the v-abl transforming gene of Abelson murine leukemia virus. By constructing recombinants between c- and v-abl retroviruses, we show that a point mutation in c-Abl is sufficient to change the myristoylated form of c-Abl into a protein able to transform fibroblasts, but not capable of transforming bone marrow or inducing Abelson disease. This activating mutation, which changes the phenylalanine at amino acid 420 to valine (F420V) found in the homologous position of v-Abl, is positioned outside of the SH3 domain, a region typically modified in transforming alleles of abl. Phenylalanine 420 is perfectly conserved among tyrosine kinases with N-terminal SH3 domains (the Src and Abl families). The equivalent position in other protein tyrosine kinases is a conserved hydrophobic residue that predicts the specific family to which that kinase belongs. Mutation of phenylalanine 420 to other hydrophobic residues activates c-Abl. Unlike other transforming variants of Abl, the F420V mutant protein is not highly phosphorylated on tyrosine. Mutation of the nearby proposed autophosphorylation site, tyrosine 412, shows that this tyrosine is not strictly required for fibroblast transformation in either F420V or SH3-deleted variants of c-Abl (IV).
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142.
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Jackson
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Paskind
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Baltimore
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D017124:Conserved Sequence; D005786:Gene Expression Regulation; D016313:Genes, abl; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010649:Phenylalanine; D010766:Phosphorylation; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics*; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry / Q000235:genetics*; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000502:physiology
D014443:Tyrosine; D010649:Phenylalanine; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl