title: p130CAS forms a signaling complex with the adapter protein CRKL in hematopoietic cells transformed by the BCR/ABL oncogene.
abstract: 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.
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: R
authors.initials: R
authors.lastname: Salgia
authors.forename: E
authors.initials: E
authors.lastname: Pisick
authors.forename: M
authors.initials: M
authors.lastname: Sattler
authors.forename: J L
authors.initials: JL
authors.lastname: Li
authors.forename: N
authors.initials: N
authors.lastname: Uemura
authors.forename: W K
authors.initials: WK
authors.lastname: Wong
authors.forename: S A
authors.initials: SA
authors.lastname: Burky
authors.forename: H
authors.initials: H
authors.lastname: Hirai
authors.forename: L B
authors.initials: LB
authors.lastname: Chen
authors.forename: J D
authors.initials: JD
authors.lastname: Griffin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001773:Blood Cells; D002460:Cell Line; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D050719:Crk-Associated Substrate Protein; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D009857:Oncogenes; D010750:Phosphoproteins / Q000378:metabolism*; D019000:Phosphotyrosine; D011506:Proteins; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C493841:BCAR1 protein, human; C493842:Bcar1 protein, mouse; C082869:CRKL protein; D050719:Crk-Associated Substrate Protein; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D050717:Retinoblastoma-Like Protein p130; D019000:Phosphotyrosine; D016044:Fusion Proteins, bcr-abl