title: Tuning of protein kinase circuitry by p38α is vital for epithelial tissue homeostasis.
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.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Celia
authors.initials: C
authors.lastname: Caballero-Franco
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Choo
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Sano
authors.forename: Patcharee
authors.initials: P
authors.lastname: Ritprajak
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizoguchi
authors.forename: Jin Mo
authors.initials: JM
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D004848:Epithelium / Q000201:enzymology* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000473:pathology; D007413:Intestinal Mucosa / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D012867:Skin / Q000473:pathology; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7
keywords: Epithelium; Intestine; Mouse; Skin; p38