title: Phosphorylation of serine palmitoyltransferase long chain-1 (SPTLC1) on tyrosine 164 inhibits its activity and promotes cell survival.
abstract: In BCR-ABL-expressing cells, sphingolipid metabolism is altered. Because the first step of sphingolipid biosynthesis occurs in the endoplasmic reticulum (ER), our objective was to identify ABL targets in the ER. A phosphoproteomic analysis of canine pancreatic ER microsomes identified 49 high scoring phosphotyrosine-containing peptides. These were then categorized in silico and validated in vitro. We demonstrated that the ER-resident human protein serine palmitoyltransferase long chain-1 (SPTLC1), which is the first enzyme of sphingolipid biosynthesis, is phosphorylated at Tyr(164) by the tyrosine kinase ABL. Inhibition of BCR-ABL using either imatinib or shRNA-mediated silencing led to the activation of SPTLC1 and to increased apoptosis in both K562 and LAMA-84 cells. Finally, we demonstrated that mutation of Tyr(164) to Phe in SPTLC1 increased serine palmitoyltransferase activity. The Y164F mutation also promoted the remodeling of cellular sphingolipid content, thereby sensitizing K562 cells to apoptosis. Our observations provide a mechanistic explanation for imatinib-mediated cell death and a novel avenue for therapeutic strategies.
authors: INSERM U1053, 33076 Bordeaux, France. said.taouji@inserm.fr
authors: Saïd
authors: S
authors: Taouji
authors: Arisa
authors: A
authors: Higa
authors: Frédéric
authors: F
authors: Delom
authors: Sandrine
authors: S
authors: Palcy
authors: François-Xavier
authors: FX
authors: Mahon
authors: Jean-Max
authors: JM
authors: Pasquet
authors: Roger
authors: R
authors: Bossé
authors: Bruno
authors: B
authors: Ségui
authors: Eric
authors: E
authors: Chevet
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D002467:Cell Nucleus / Q000201:enzymology; D002470:Cell Survival; D002518:Ceramides / Q000378:metabolism; D004285:Dogs; D019008:Drug Resistance, Neoplasm; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006056:Golgi Apparatus / Q000201:enzymology; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D020543:Proteome / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D051102:Serine C-Palmitoyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D002518:Ceramides; D010446:Peptide Fragments; D010879:Piperazines; D020543:Proteome; D011743:Pyrimidines; D034741:RNA, Small Interfering; D019000:Phosphotyrosine; D000068877:Imatinib Mesylate; C487784:SPTLC1 protein, human; D051102:Serine C-Palmitoyltransferase; D016044:Fusion Proteins, bcr-abl
keywords: Apoptosis; Endoplasmic Reticulum (ER); Imatinib; Protein Kinases; Protein Phosphorylation; SPTLC1; Sphingolipid
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