Interferon Induction of TAP1

The Phosphatase SHP-1 Regulates Crossover Between the IFN-/ß and the IFN- Signal-Transduction Pathways

From the Department of Pathology and the Molecular Cardiobiology Program, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Conn.

Correspondence to David R. Johnson, 454 BCMM, Yale University School of Medicine, 295 Congress Ave, New Haven, CT 06510. E-mail johnson{at}biomed.med.yale.edu

Abstract—Interferon (IFN)- and IFN-/ß induction of the transporter associated with antigen processing-1 (TAP1) promoter was compared in HeLa cells and endothelial cells (ECs). In HeLa cells, IFN- acts through Stat1/Stat1 homodimers binding to the gamma activating sequence (GAS) and IFN-/ß acts through Stat1/Stat2/p48 binding to the IFN-stimulated response element (ISRE). In ECs, however, IFN- and IFN-/ß act through both the GAS and ISRE. The basis of the IFN signaling crossover in ECs was investigated. HeLa and ECs contain similar ratios of Stat1 to Stat2 proteins, and IFN-/ß also activates the same Janus kinases (JAKs) (Jak1 and tyrosine kinase (Tyk) 2 but not Jak2). However, IFN-/ß activates more Stat1 than does IFN- in ECs, whereas the reverse occurs in HeLa, and expression of the IFN-/ß receptor-associated phosphatase SHP-1 is much lower in ECs than HeLa cells. Overexpression of SHP-1 in ECs blocks IFN-/ß signaling through GAS, and expression of a dominant negative SHP-1 in HeLa cells permits IFN-/ß signaling through GAS, demonstrating a role for SHP-1 in regulating crossovers between the IFN-/ß and IFN- signaling pathways.

Key Words: endothelial cell • interferon • MHC class I • transporter associated with antigen processing (TAP) • phosphatase

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