Tyrosine phosphorylation of CRKL in Philadelphia+ leukemia.
The chimeric BCR/ABL protein is characteristic of Philadelphia (Ph)+ leukemia because it is the direct product of the Ph translocation and it has been shown to play a causal role in the genesis of leukemia. The BCR/ABL protein exhibits a deregulated tyrosine-kinase activity capable of phosphorylating different cellular substrates in vivo and in vitro. CRKL, an adaptor protein consisting of SH2 and SH3 domains in the absence of a catalytic domain, is one potential in vivo substrate of BCR/ABL. Previous experiments have shown that CRKL is phosphorylated on tyrosine in the chronic myelogenous leukemia (CML) cell line K562 and that CRKL is a substrate for ABL and for BCR/ABL in COS-1 cells. In the current study, we show that in peripheral blood cells a direct correlation exists between the presence of BCR/ABL and the phosphorylation status of CRKL. In Ph- peripheral blood cells, CRKL is present only in the nonphosphorylated form. In contrast, all BCR/ABL+ CML and acute lymphoblastic leukemia patient samples examined showed clear tyrosine-phosphorylation of CRKL. This result strongly suggests that CRKL is a biologically significant substrate for BCR/ABL and is likely to play a major role in the development of Ph+ leukemia.
ten Hoeve
J
J
Department of Pathology, Childrens Hospital of Los Angeles.
Arlinghaus
R B
RB
Guo
J Q
JQ
Heisterkamp
N
N
Groffen
J
J
D048868:Adaptor Proteins, Signal Transducing; D015153:Blotting, Western; D016044:Fusion Proteins, bcr-abl / Q000097:blood; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood*; D009687:Nuclear Proteins / Q000097:blood* / Q000235:genetics; D010766:Phosphorylation; D019000:Phosphotyrosine; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000097:blood
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D009687:Nuclear Proteins; D019000:Phosphotyrosine; D014443:Tyrosine; D016044:Fusion Proteins, bcr-abl