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Release of nonmuscle myosin II from the cytosolic domain of tumor necrosis factor receptor 2 is required for target gene expression.
Sci Signal. 2013 Jul 16; 6(284):ra60.SS

Abstract

Tumor necrosis factor-α (TNF-α) elicits its biological activities through activation of TNF receptor 1 (TNFR1, also known as p55) and TNFR2 (also known as p75). The activities of both receptors are required for the TNF-α-induced proinflammatory response. The adaptor protein TNFR-associated factor 2 (TRAF2) is critical for either p55- or p75-mediated activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, as well as for target gene expression. We identified nonmuscle myosin II (myosin) as a binding partner of p75. TNF-α-dependent signaling by p75 and induction of target gene expression persisted substantially longer in cells deficient in myosin regulatory light chain (MRLC; a component of myosin) than in cells replete in myosin. In resting endothelial cells, myosin was bound constitutively to the intracellular region of p75, a region that overlaps with the TRAF2-binding domain, and TNF-α caused the rapid dissociation of myosin from p75. At early time points after exposure to TNF-α, p75 activated Rho-associated kinase 1 (ROCK1). Inhibition of ROCK1 activity blocked TNF-α-dependent phosphorylation of MRLC and the dissociation of myosin from p75. ROCK1-dependent release of myosin was necessary for the TNF-α-dependent recruitment of TRAF2 to p75 and for p75-specific activation of NF-κB and MAPK signaling. Thus, our findings have revealed a previously uncharacterized, noncanonical regulatory function of myosin in cytokine signaling.

Authors+Show Affiliations

Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23861542

Citation

Chandrasekharan, Unni M., et al. "Release of Nonmuscle Myosin II From the Cytosolic Domain of Tumor Necrosis Factor Receptor 2 Is Required for Target Gene Expression." Science Signaling, vol. 6, no. 284, 2013, pp. ra60.
Chandrasekharan UM, Dechert L, Davidson UI, et al. Release of nonmuscle myosin II from the cytosolic domain of tumor necrosis factor receptor 2 is required for target gene expression. Sci Signal. 2013;6(284):ra60.
Chandrasekharan, U. M., Dechert, L., Davidson, U. I., Waitkus, M., Mavrakis, L., Lyons, K., Beach, J. R., Li, X., Egelhoff, T. T., Fox, P. L., & DiCorleto, P. E. (2013). Release of nonmuscle myosin II from the cytosolic domain of tumor necrosis factor receptor 2 is required for target gene expression. Science Signaling, 6(284), ra60. https://doi.org/10.1126/scisignal.2003743
Chandrasekharan UM, et al. Release of Nonmuscle Myosin II From the Cytosolic Domain of Tumor Necrosis Factor Receptor 2 Is Required for Target Gene Expression. Sci Signal. 2013 Jul 16;6(284):ra60. PubMed PMID: 23861542.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Release of nonmuscle myosin II from the cytosolic domain of tumor necrosis factor receptor 2 is required for target gene expression. AU - Chandrasekharan,Unni M, AU - Dechert,Lisa, AU - Davidson,Uchechukwu I, AU - Waitkus,Matthew, AU - Mavrakis,Lori, AU - Lyons,Katherine, AU - Beach,Jordan R, AU - Li,Xiaoxia, AU - Egelhoff,Thomas T, AU - Fox,Paul L, AU - DiCorleto,Paul E, Y1 - 2013/07/16/ PY - 2013/7/18/entrez PY - 2013/7/19/pubmed PY - 2014/2/5/medline SP - ra60 EP - ra60 JF - Science signaling JO - Sci Signal VL - 6 IS - 284 N2 - Tumor necrosis factor-α (TNF-α) elicits its biological activities through activation of TNF receptor 1 (TNFR1, also known as p55) and TNFR2 (also known as p75). The activities of both receptors are required for the TNF-α-induced proinflammatory response. The adaptor protein TNFR-associated factor 2 (TRAF2) is critical for either p55- or p75-mediated activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, as well as for target gene expression. We identified nonmuscle myosin II (myosin) as a binding partner of p75. TNF-α-dependent signaling by p75 and induction of target gene expression persisted substantially longer in cells deficient in myosin regulatory light chain (MRLC; a component of myosin) than in cells replete in myosin. In resting endothelial cells, myosin was bound constitutively to the intracellular region of p75, a region that overlaps with the TRAF2-binding domain, and TNF-α caused the rapid dissociation of myosin from p75. At early time points after exposure to TNF-α, p75 activated Rho-associated kinase 1 (ROCK1). Inhibition of ROCK1 activity blocked TNF-α-dependent phosphorylation of MRLC and the dissociation of myosin from p75. ROCK1-dependent release of myosin was necessary for the TNF-α-dependent recruitment of TRAF2 to p75 and for p75-specific activation of NF-κB and MAPK signaling. Thus, our findings have revealed a previously uncharacterized, noncanonical regulatory function of myosin in cytokine signaling. SN - 1937-9145 UR - https://www.unboundmedicine.com/medline/citation/23861542/Release_of_nonmuscle_myosin_II_from_the_cytosolic_domain_of_tumor_necrosis_factor_receptor_2_is_required_for_target_gene_expression_ L2 - https://stke.sciencemag.org/cgi/pmidlookup?view=long&pmid=23861542 DB - PRIME DP - Unbound Medicine ER -