Establishment of extracellular signal-regulated kinase 1/2 bistability and sustained activation through Sprouty 2 and its relevance for epithelial function.

Molecular and Cellular Biology
Weimin LiuRafeul Alam

Abstract

Our objective was to establish an experimental model of a self-sustained and bistable extracellular signal-regulated kinase 1/2 (ERK1/2) signaling process. A single stimulation of cells with cytokines causes rapid ERK1/2 activation, which returns to baseline in 4 h. Repeated stimulation leads to sustained activation of ERK1/2 but not Jun N-terminal protein kinase (JNK), p38, or STAT6. The ERK1/2 activation lasts for 3 to 7 days and depends upon a positive-feedback mechanism involving Sprouty 2. Overexpression of Sprouty 2 induces, and its genetic deletion abrogates, ERK1/2 bistability. Sprouty 2 directly activates Fyn kinase, which then induces ERK1/2 activation. A genome-wide microarray analysis shows that the bistable phospho-ERK1/2 (pERK1/2) does not induce a high level of gene transcription. This is due to its nuclear exclusion and compartmentalization to Rab5+ endosomes. Cells with sustained endosomal pERK1/2 manifest resistance against growth factor withdrawal-induced cell death. They are primed for heightened cytokine production. Epithelial cells from cases of human asthma and from a mouse model of chronic asthma manifest increased pERK1/2, which is associated with Rab5+ endosomes. The increase in pERK1/2 was associated ...Continue Reading

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Citations

Jan 21, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Nicholas GoplenRafeul Alam
Nov 26, 2010·Immunology and Allergy Clinics of North America·Rafeul Alam
Oct 7, 2015·Scientific Reports·Mohamed Raafet AmmarNicolas Vitale
Dec 3, 2010·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·R Alam, M M Gorska
Jan 27, 2015·The Journal of Allergy and Clinical Immunology·Christina A ChristiansonRafeul Alam
Oct 6, 2016·The Journal of Allergy and Clinical Immunology·Weimin LiuRafeul Alam
Dec 12, 2012·Current Opinion in Allergy and Clinical Immunology·Christina A Christianson, Rafeul Alam
Dec 12, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Lei GuoRafeul Alam

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