TY - JOUR
T1 - ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses
AU - Papoutsopoulou, Stamatia
AU - Symons, Antony
AU - Tharmalingham, Tharsana
AU - Belich, Monica P.
AU - Kaiser, Frank
AU - Kioussis, Dimitris
AU - O'Garra, Anne
AU - Tybulewicz, Victor
AU - Ley, Steven C.
N1 - Funding Information:
We thank T. Kitamura and P. Tsichlis for reagents; S. Beinke and B. Seddon (Division of Immune Cell Biology, NIMR) for critical reading of the manuscript; A. Garefalaki and U. Menzel (Division of Molecular Immunology, NIMR) for help with culturing targeted embryonic stem cells; M. Holman (Division of Immunoregulation, NIMR) for advice on LPS injections; and the NIMR Photographics department, NIMR Biological Services and other members of the Ley laboratory for help during the course of this work. Supported by the UK Medical Research Council and Arthritis Research Campaign (L0549 to A.S. and 16053 to F.K.).
PY - 2006/6
Y1 - 2006/6
N2 - The TPL-2 MEK kinase is essential for activation of the Erk MAP kinase pathway during innate immune responses. TPL-2 is found in complex with ABIN-2 (A20-binding inhibitor of NF-κB 2). Here, using antigen-presenting cells from ABIN-2-deficient mice, we show that ABIN-2 was required for optimal activation of Erk induced by receptors that signal via TPL-2, including Toll-like receptor 4 and tumor necrosis factor receptor 1 in macrophages, and CD40 in B cells. ABIN-2 was necessary for the maintenance of TPL-2 protein stability. In contrast, ABIN-2 deficiency did not affect agonist-induced regulation of transcription factor NF-κB. Stimulation of ABIN-2-deficient macrophages via Toll-like receptor 4 showed that different thresholds of Erk signaling were required for optimal induction of tumor necrosis factor and interleukin 1β. Thus, ABIN-2 acts to positively regulate the Erk signaling potential by stabilizing TPL-2.
AB - The TPL-2 MEK kinase is essential for activation of the Erk MAP kinase pathway during innate immune responses. TPL-2 is found in complex with ABIN-2 (A20-binding inhibitor of NF-κB 2). Here, using antigen-presenting cells from ABIN-2-deficient mice, we show that ABIN-2 was required for optimal activation of Erk induced by receptors that signal via TPL-2, including Toll-like receptor 4 and tumor necrosis factor receptor 1 in macrophages, and CD40 in B cells. ABIN-2 was necessary for the maintenance of TPL-2 protein stability. In contrast, ABIN-2 deficiency did not affect agonist-induced regulation of transcription factor NF-κB. Stimulation of ABIN-2-deficient macrophages via Toll-like receptor 4 showed that different thresholds of Erk signaling were required for optimal induction of tumor necrosis factor and interleukin 1β. Thus, ABIN-2 acts to positively regulate the Erk signaling potential by stabilizing TPL-2.
UR - http://www.scopus.com/inward/record.url?scp=33744455163&partnerID=8YFLogxK
U2 - 10.1038/ni1334
DO - 10.1038/ni1334
M3 - Journal articles
C2 - 16633345
AN - SCOPUS:33744455163
SN - 1529-2908
VL - 7
SP - 606
EP - 615
JO - Nature Immunology
JF - Nature Immunology
IS - 6
ER -
