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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Linker for Activation of T-cell Family Member2 (LAT2) a Lipid Raft Adaptor Protein for AKT Signaling, Is an Early Mediator of Alkylphospholipid Anti-leukemic Activity

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Thome, Carolina H. [1, 2] ; dos Santos, Guilherme A. [1, 3] ; Ferreira, Germano A. [1, 4] ; Scheucher, Priscila S. [1, 4] ; Izumi, Clarice [1] ; Leopoldino, Andreia M. [5] ; Simao, Ana Maria [6] ; Ciancaglini, Pietro [6] ; de Oliveira, Kleber T. [7] ; Chin, Alice [8] ; Hanash, Samir M. [8] ; Falcao, Roberto P. [1, 3] ; Rego, Eduardo M. [1, 3] ; Greene, Lewis J. [1, 4] ; Faca, Vitor M. [9, 1]
Total Authors: 15
Affiliation:
[1] Fundacao Hemoctr Ribeirao Preto, Inst Nacl Ciencia & Tecnol Celulas Tronco & Terap, BR-14051140 Ribeirao Preto, SP - Brazil
[2] Univ Fed Sao Paulo, Escola Paulista Med, Dept Bioquim, BR-04039002 Sao Paulo - Brazil
[3] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Clin Med, BR-14049900 Ribeirao Preto, SP - Brazil
[4] Fac Med Ribeirao Preto, Dept Biol Celular & Mol & Bioagentes Patogen, BR-14049900 Ribeirao Preto, SP - Brazil
[5] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Anal Clin Toxicol & Bromatol, BR-14040903 Ribeirao Preto, SP - Brazil
[6] Univ Sao Paulo, Fac Filosofia Ciencias & Letras Ribeirao Preto, Dept Quim, BR-14040901 Ribeirao Preto, SP - Brazil
[7] Univ Fed Sao Carlos, Ctr Ciencias Exatas & Tecnol, Dept Quim, BR-13565905 Sao Carlos, SP - Brazil
[8] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 - USA
[9] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Bioquim & Imunol, BR-14049900 Ribeirao Preto, SP - Brazil
Total Affiliations: 9
Document type: Journal article
Source: MOLECULAR & CELLULAR PROTEOMICS; v. 11, n. 12, SI, p. 1898-1912, DEC 2012.
Web of Science Citations: 15
Abstract

Lipid rafts are highly ordered membrane domains rich in cholesterol and sphingolipids that provide a scaffold for signal transduction proteins; altered raft structure has also been implicated in cancer progression. We have shown that 25 mu M 10-(octyloxy) decyl-2-(trimethylammonium) ethyl phosphate (ODPC), an alkylphospholipid, targets high cholesterol domains in model membranes and induces apoptosis in leukemia cells but spares normal hematopoietic and epithelial cells under the same conditions. We performed a quantitative (SILAC) proteomic screening of ODPC targets in a lipid-raft-enriched fraction of leukemic cells to identify early events prior to the initiation of apoptosis. Six proteins, three with demonstrated palmitoylation sites, were reduced in abundance. One, the linker for activation of T-cell family member 2 (LAT2), is an adaptor protein associated with lipid rafts in its palmitoylated form and is specifically expressed in B lymphocytes and myeloid cells. Interestingly, LAT2 is not expressed in K562, a cell line more resistant to ODPC-induced apoptosis. There was an early loss of LAT2 in the lipid-raft-enriched fraction of NB4 cells within 3 h following treatment with 25 mu M ODPC. Subsequent degradation of LAT2 by proteasomes was observed. Twenty-five mu M ODPC inhibited AKT activation via myeloid growth factors, and LAT2 knockdown in NB4 cells by shRNA reproduced this effect. LAT2 knockdown in NB4 cells also decreased cell proliferation and increased cell sensitivity to ODPC (7.5X), perifosine (3X), and arsenic trioxide (8.5X). Taken together, these data indicate that LAT2 is an early mediator of the anti-leukemic activity of alkylphospholipids and arsenic trioxide. Thus, LAT2 may be used as a target for the design of drugs for cancer therapy. Molecular \& Cellular Proteomics 11: 10.1074/mcp.M112.019661, 1898-1912, 2012. (AU)