Molecular Cell
Volume 37, Issue 4, 26 February 2010, Pages 551-566
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Article
Direct Activation of TACE-Mediated Ectodomain Shedding by p38 MAP Kinase Regulates EGF Receptor-Dependent Cell Proliferation

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Summary

Inflammatory stimuli activate ectodomain shedding of TNF-α, L-selectin, and other transmembrane proteins. We show that p38 MAP kinase, which is activated in response to inflammatory or stress signals, directly activates TACE, a membrane-associated metalloprotease that is also known as ADAM17 and effects shedding in response to growth factors and Erk MAP kinase activation. p38α MAP kinase interacts with the cytoplasmic domain of TACE and phosphorylates it on Thr735, which is required for TACE-mediated ectodomain shedding. Activation of TACE by p38 MAP kinase results in the release of TGF-α family ligands, which activate EGF receptor signaling, leading to enhanced cell proliferation. Conversely, depletion of p38α MAP kinase activity suppresses EGF receptor signaling and downstream Erk MAP kinase signaling, as well as autocrine EGF receptor-dependent proliferation. Autocrine EGF receptor activation through TACE-mediated ectodomain shedding intimately links inflammation and cancer progression and may play a role in stress and conditions that relate to p38 MAP kinase activation.

Highlights

► Activation of p38 MAPK induces TACE-mediated ectodomain shedding of TGF-α ligands ► The metalloprotease TACE acts as a direct target of p38 MAP kinase ► p38α MAPK associates with and phosphorylates TACE, thus activating TACE ► p38 MAPK signaling activates EGFR, linking inflammation to cancer progression

SIGNALING
CELLCYCLE
HUMDISEASE

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