Fist/Hipk3: A FAS/Fadd-Interacting Serine/Threonine Kinase That Induces Fadd Phosphorylation and Inhibits FAS-Mediated Jun Nh2-Terminal Kinase Activation

doi:10.1084/jem.192.8.1165

Published online 16 October 2000.

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© The Rockefeller University Press, 0022-1007/2000/10/1165/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 8, October 16, 2000 1165-1174

Original Article

Fist/Hipk3: A FAS/Fadd-Interacting Serine/Threonine Kinase That Induces Fadd Phosphorylation and Inhibits FAS-Mediated Jun Nh₂-Terminal Kinase Activation

Véronique Rochat-Steiner^a, Karin Becker^a, Olivier Micheau^a, Pascal Schneider^a, Kim Burns^a, and Jürg Tschopp^a

^a Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, CH-1066 Epalinges, Switzerland
Institute of Biochemistry, University of Lausanne, Ch. des Boveresses 155, CH-1066 Epalinges, Switzerland.41-21-692-570541-21-692-5738

Fas is a cell surface death receptor that signals apoptosis.Several proteins have been identified that bind to the cytoplasmicdeath domain of Fas. Fas-associated death domain (FADD), whichcouples Fas to procaspase-8, and Daxx, which couples Fas tothe Jun NH₂-terminal kinase pathway, bind independently to theFas death domain. We have identified a 130-kD kinase designatedFas-interacting serine/threonine kinase/homeodomain-interactingprotein kinase (FIST/HIPK3) as a novel Fas-interacting protein.Binding to Fas is mediated by a conserved sequence in the COOHterminus of the protein. FIST/HIPK3 is widely expressed in mammaliantissues and is localized both in the nucleus and in the cytoplasm.In transfected cell lines, FIST/HIPK3 causes FADD phosphorylation,thereby promoting FIST/HIPK3–FADD–Fas interaction.Although Fas ligand–induced activation of Jun NH₂-terminalkinase is impaired by overexpressed active FIST/HIPK3, celldeath is not affected. These results suggest that Fas-associatedFIST/HIPK3 modulates one of the two major signaling pathwaysof Fas.

Key Words: Fas/CD95 • apoptosis • kinase • Jun NH₂-terminal kinase • signal transduction

Abbreviations used in this paper: aa, amino acid(s); DED, deatheffector domain; FADD, Fas-associated death domain; FasL, Fasligand; FIST, Fas-interacting serine/threonine kinase; HIPK,homeodomain-interacting protein kinase; JNK, Jun NH₂-terminalkinase.

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