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

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

Author Thomé, Carolina Hassibe Autor UNIFESP Google Scholar
Santos, Guilherme A. dos Google Scholar
Ferreira, Germano A. Google Scholar
Scheucher, Priscila S. Google Scholar
Izumi, Clarice Google Scholar
Leopoldino, Andreia M. Google Scholar
Simao, Ana Maria Google Scholar
Ciancaglini, Pietro Google Scholar
Oliveira, Kleber T. de Google Scholar
Chin, Alice Google Scholar
Hanash, Samir M. Google Scholar
Falcao, Roberto P. Google Scholar
Rego, Eduardo M. Google Scholar
Greene, Lewis J. Google Scholar
Faca, Vitor M. Google Scholar
Institution Fundacao Hemoctr Ribeirao Preto
Universidade Federal de São Paulo (UNIFESP)
Universidade de São Paulo (USP)
Fac Med Ribeirao Preto
Universidade Federal de São Carlos (UFSCar)
Fred Hutchinson Canc Res Ctr
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.
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Grant number FAPESP: 07/58649-1
FAPESP: 2011/07387-2
FAPESP: 2011/09718-6
Date 2012-12-01
Published in Molecular & Cellular Proteomics. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 11, n. 12, p. 1898-1912, 2012.
ISSN 1535-9476 (Sherpa/Romeo, impact factor)
Publisher Amer Soc Biochemistry Molecular Biology Inc
Extent 1898-1912
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000313557000031

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