Evidence for regulation of the human ABL tyrosine kinase by a cellular inhibitor.
Phosphotyrosine cannot be detected on normal human ABL protein-tyrosine kinases, but activated oncogenic forms of the human ABL protein are phosphorylated on tyrosine in vivo. Activation of ABL can occur by substitution of the ABL first exon with breakpoint cluster region (BCR) sequences or by deletion of the noncatalytic SH3 (src homology region 3) domain. An alternative mode for the activation of the ABL kinases is hyperexpression at greater than 500-fold over endogenous levels. This is not a consequence of transphosphorylation of the hyperexpressed ABL molecules. ABL proteins translated in vitro lack phosphotyrosine, but tyrosine kinase activity is uncovered after immunoprecipitation and removal of lysate components. The rates of dephosphorylation of ABL and BCR-ABL fusion protein by phosphotyrosine-specific phosphatases are approximately the same. These combined results indicate that inhibition of ABL activity is reversible and suggest that a cellular component interacts noncovalently with ABL to inhibit its autophosphorylation.
Pendergast
A M
AM
Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90024.
Muller
A J
AJ
Havlik
M H
MH
Clark
R
R
McCormick
F
F
Witte
O N
ON
D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D015870:Gene Expression; D066298:In Vitro Techniques; D007313:Insecta; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D051562:Proto-Oncogene Proteins c-bcr; D011994:Recombinant Proteins / Q000378:metabolism; D012156:Reticulocytes / Q000201:enzymology; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D019000:Phosphotyrosine; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D051562:Proto-Oncogene Proteins c-bcr