title: Imatinib restores VASP activity and its interaction with Zyxin in BCR-ABL leukemic cells.
abstract: Vasodilator-stimulated phosphoprotein (VASP) and Zyxin are interacting proteins involved in cellular adhesion and motility. PKA phosphorylates VASP at serine 157, regulating VASP cellular functions. VASP interacts with ABL and is a substrate of the BCR-ABL oncoprotein. The presence of BCR-ABL protein drives oncogenesis in patients with chronic myeloid leukemia (CML) due to a constitutive activation of tyrosine kinase activity. However, the function of VASP and Zyxin in BCR-ABL pathway and the role of VASP in CML cells remain unknown. In vitro experiments using K562 cells showed the involvement of VASP in BCR-ABL signaling. VASP and Zyxin inhibition decreased the expression of anti-apoptotic proteins, BCL2 and BCL-XL. Imatinib induced an increase in phosphorylation at Ser157 of VASP and decreased VASP and BCR-ABL interaction. VASP did not interact with Zyxin in K562 cells; however, after Imatinib treatment, this interaction was restored. Corroborating our data, we demonstrated the absence of phosphorylation at Ser157 in VASP in the bone marrow of CML patients, in contrast to healthy donors. Phosphorylation of VASP on Ser157 was restored in Imatinib responsive patients though not in the resistant patients. Therefore, we herein identified a possible role of VASP in CML pathogenesis, through the regulation of BCR-ABL effector proteins or the absence of phosphorylation at Ser157 in VASP.
authors.affiliation: Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Bernusso
authors.affiliation: Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: João A
authors.initials: JA
authors.lastname: Machado-Neto
authors.affiliation: Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Fernando V
authors.initials: FV
authors.lastname: Pericole
authors.affiliation: Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Karla P
authors.initials: KP
authors.lastname: Vieira
authors.affiliation: Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Adriana S S
authors.initials: AS
authors.lastname: Duarte
authors.affiliation: Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Traina
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT, USA.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Hansen
authors.affiliation: Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Sara T
authors.initials: ST
authors.lastname: Olalla Saad
authors.affiliation: Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil. Electronic address: kabarcellos@gmail.com.
authors.forename: Karin S A
authors.initials: KS
authors.lastname: Barcellos
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000473:pathology*; D008840:Microfilament Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D060589:Zyxin / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D001549:Benzamides; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010879:Piperazines; D011743:Pyrimidines; C092842:ZYX protein, human; D060589:Zyxin; D051020:bcl-X Protein; D000098662:Vasodilator-Stimulated Phosphoprotein; D010768:Phosphoserine; D000068877:Imatinib Mesylate; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl
keywords: Apoptosis; BCR–ABL; Leukemia; VASP; Vasodilator-stimulated phosphoprotein; Zyxin