Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Philadelphia chromosome (Ph) translocation generates a chimeric tyrosine kinase oncogene, BCR/ABL, which causes chronic myelogenous leukemia (CML) and a type of acute lymphoblastic leukemia (ALL). In primary samples from virtually all patients with CML or Ph+ALL, the CRKL adapter protein is tyrosine phosphorylated and physically associated with p210(BCR/ABL). CRKL has one SH2 domain and two SH3 domains and is structurally related to c-CRK-II (CRK) and the v-Crk oncoprotein. We have previously shown that CRKL, but not the related adapter protein c-CRK, is tyrosine phosphorylated in cell lines transformed by BCR/ABL, and that CRKL binds to BCR/ABL through the CRKL-SH3 domains. Furthermore, the CRKL-SH2 domain has been shown to bind one or more cellular proteins, one of which is p120(CBL). Here we demonstrate that another cellular protein linked to BCR/ABL through the CRKL-SH2 domain is p130(CAS). p130(CAS) was found to be tyrosine phosphorylated and associated with CRKL in BCR/ABL expressing cell lines and in samples obtained from CML and ALL patients, but not in samples from controls. In both normal and BCR/ABL transformed cells, p130(CAS) was detected in focal adhesion-like structures, as was BCR/ABL. In normal cells, the focal adhesion proteins tensin, p125(FAK), and paxillin constitutively associated with p130(CAS). However, in BCR/ABL transformed cells, the interaction between p130(CAS) and tensin was disrupted, while the associations between p130(CAS), p125(FAK), and paxillin were unaffected. These results suggest that the BCR/ABL oncogene could alter the function of p130(CAS) in at least three ways: tyrosine phosphorylation, inducing constitutive binding of CRKL to a domain in p130(CAS) containing Tyr-X-X-Pro motifs (substrate domain), and disrupting the normal interaction of p130(CAS) with the focal adhesion protein tensin. These alterations in the structure of signaling proteins in focal adhesion like structures could contribute to the known adhesion abnormalities in CML cells.
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PMID:p130CAS forms a signaling complex with the adapter protein CRKL in hematopoietic cells transformed by the BCR/ABL oncogene. 881 Feb 78

CT-10 regulator of kinase (CRK) proteins play important roles in human cancer metastasis and invasion. Moreover, CRK proteins are the major phosphorylation substrates of ABL kinase and its oncogenic mutant BCR-ABL kinase. The interaction between CRK and BCR-ABL plays important roles in chronic myeloid leukemia. Hence, inhibiting the interaction of CRK with BCR-ABL is an attractive way to attenuate cancer metastasis. Herein, we report the development of a peptide inhibitor, PRM-3, targeting the interaction between CRK-II and ABL kinase. PRM-3 binds to the N-terminal SH3 (nSH3) domain in CRK-II with a 10 nM affinity and prevents the interaction between CRK-II and ABL kinase. An in vitro biochemical assay demonstrated that PRM-3 inhibits the ABL-dependent phosphorylation of CRK-II more effectively than imatinib. Remarkably, PRM-3 also inhibited the CRK phosphorylation by T315I-ABL kinase, which is resistant to all first- and second-generation tyrosine kinase inhibitors. Our study provides a promising alternative approach to overcome the drug resistance of ABL kinase.
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PMID:Structure-guided design of a potent peptide inhibitor targeting the interaction between CRK and ABL kinase. 3010 42