title: The membrane-proximal KXGFFKR motif of α-integrin mediates chemoresistance.
abstract: Cell adhesion-mediated drug resistance contributes to minimal residual disease and relapse in hematological malignancies. Here, we show that adhesion of Jurkat T-acute lymphoblastic leukemia cells to substrates engaging α4β1-integrin or α5β1-integrin promotes chemoresistance to doxorubicin-induced apoptosis. Reconstituted expression of α4δ, a truncated α4-integrin with KXGFFKR as the cytoplasmic motif, in α4-deficient cells promoted chemoresistance to doxorubicin in a manner independent of α4-mediated adhesion. The adhesion-independent chemoresistance did not require β1-integrin as the heterodimeric pair, since expression of Tacδ, a monomeric nonintegrin transmembrane protein fused to the juxtamembrane KXGFFKR, was sufficient to reproduce the phenomenon. The requirement for integrin-mediated adhesion in stimulation of Akt phosphorylation and activation was bypassed for cells expressing α4δ and Tacδ. Cells expressing α4δ and Tacδ exhibited a high influx of extracellular Ca(2+), and inhibition of Ca(2+) channels with verapamil attenuated the adhesion-independent chemoresistance. Tacδ cells also exhibited greater rates of drug efflux. α4δ and Tacδ interacted with the Ca(2+)-binding protein calreticulin, in a manner dependent on the KXGFFKR motif. Adhesion-mediated engagement of α4-integrins promoted an increased calreticulin-α4 association and greater influx of extracellular Ca(2+) than in nonadherent cells. The α-integrin KXGFFKR motif is involved in adhesion-mediated control of chemoresistance in T cells.
authors.affiliation: Departments of Pediatrics.
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Liu
authors.forename: Pascal
authors.initials: P
authors.lastname: Leclair
authors.forename: Shyong Quin
authors.initials: SQ
authors.lastname: Yap
authors.forename: Chinten James
authors.initials: CJ
authors.lastname: Lim
mesh_terms: D000595:Amino Acid Sequence; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D037282:Calreticulin / Q000378:metabolism; D002448:Cell Adhesion; D002470:Cell Survival; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D039441:Integrin alpha4 / Q000737:chemistry / Q000378:metabolism*; D039482:Integrin alpha5 / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000096:biosynthesis; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D020746:Calcium Channels, L-Type; D037282:Calreticulin; C508017:IL2RA protein, human; D039482:Integrin alpha5; D019012:Integrin beta1; D053645:Interleukin-2 Receptor alpha Subunit; D010446:Peptide Fragments; D039441:Integrin alpha4; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt