Active (p)CrkL is overexpressed in human malignancies: potential role as a surrogate parameter for therapeutic tyrosine kinase inhibition.
CrkL is a nuclear adaptor and transcriptional activator in Bcr-Abl expressing cells and constitutes the major tyrosine phosphorylated protein in CML, but the expression and biological function of CrkL in other malignancies is largely unknown. Using immunohistochemistry, we have analyzed the protein expression of activated (p)CrkL in normal and malignant tissues. We then treated K562 leukemia cells with imatinib to analyze the effect of tyrosine kinase inhibition on CrkL activation. pCrkL expression was predominantly epithelial and detected in the majority of non-malignant prostate (79%), 49% of colon biopsies, 36% of skin biopsies, and 41% of samples obtained from normal brain. Protein expression was, however, considerably less frequent in normal breast (18%), lung (16%) and ovarian (12%) tissues. In contrast to their corresponding benign tissues, pCrkL expression was significantly more common in breast cancer samples (49%, p<0.0001; Fisher's exact test), lung carcinomas (55%, p=0.0002), lymphatic tissues (80% vs. 10%, p=0.012), skin cancer (67%, p=0.020), ovarian malignomas (50%, p<0.0001) and colon carcinomas (63%, p<0.03). By contrast, activated CrkL was significantly less frequent in prostate carcinoma samples when compared to corresponding non-malignant prostatic tissues (14% vs. 79%, p<0.0001). pCrkL expression was abrogated in K562 cells with the addition of the tyrosine kinase inhibitor imatinib, which indicates that phosphorylation of CrkL is mediated through targets of therapeutic TK inhibition. We hypothesize that pCrkL is selectively up-regulated in a number of malignant tumor entities and involved in malignant transformation. We further suggest that pCrkL might serve as a potential surrogate parameter for the efficacy of therapeutic TK inhibition.
Singer
Christian F
CF
Division of Senology, University of Vienna, Vienna, Austria. christian.singer@meduniwien.ac.at
Hudelist
Gernot
G
Lamm
Wolfgang
W
Mueller
Ruth
R
Handl
Claudia
C
Kubista
Ernst
E
Czerwenka
Klaus
K
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000187:drug effects*; D011743:Pyrimidines / Q000627:therapeutic use; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; D014408:Biomarkers, Tumor; C082869:CRKL protein; D009687:Nuclear Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases