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J Biol Chem. 2013 Aug 16;288(33):23788-97. doi: 10.1074/jbc.M113.452029. Epub 2013 Jul 8.

Tuning of protein kinase circuitry by p38α is vital for epithelial tissue homeostasis.

Author information

1
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.

Abstract

The epithelium of mucosal and skin surfaces serves as a permeability barrier and affords mechanisms for local immune defense. Crucial to the development and maintenance of a properly functioning epithelium is the balance of cell proliferation, differentiation, and death. Here we show that this balance depends on cross-regulatory interactions among multiple protein kinase-mediated signals and their coordinated transmission. From an investigation of conditional gene knock-out mice, we find that epithelial-specific loss of the protein kinase p38α leads to aberrant activation of TAK1, JNK, EGF receptor, and ERK in distinct microanatomical areas of the intestines and skin. Consequently, the epithelial tissues display excessive proliferation, inadequate differentiation, and sensitivity to apoptosis. These anomalies leave the tissue prone to damage and collapse at the trigger of an environmental insult. The vulnerability of p38α-deficient epithelium predicts adverse effects of long term pharmacological p38α inhibition; yet such limitations could be overcome by concomitant blockade of one or more of the dysregulated protein kinase signaling pathways.

KEYWORDS:

Epithelium; Intestine; Mouse; Skin; p38

PMID:
23836897
PMCID:
PMC3745325
DOI:
10.1074/jbc.M113.452029
[Indexed for MEDLINE]
Free PMC Article
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