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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.

ABSTRACT: Tumor necrosis factor-? (TNF-?) 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-?-induced proinflammatory response. The adaptor protein TNFR-associated factor 2 (TRAF2) is critical for either p55- or p75-mediated activation of nuclear factor ?B (NF-?B) 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-?-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-? caused the rapid dissociation of myosin from p75. At early time points after exposure to TNF-?, p75 activated Rho-associated kinase 1 (ROCK1). Inhibition of ROCK1 activity blocked TNF-?-dependent phosphorylation of MRLC and the dissociation of myosin from p75. ROCK1-dependent release of myosin was necessary for the TNF-?-dependent recruitment of TRAF2 to p75 and for p75-specific activation of NF-?B and MAPK signaling. Thus, our findings have revealed a previously uncharacterized, noncanonical regulatory function of myosin in cytokine signaling.

SUBMITTER: Chandrasekharan UM

PROVIDER: S-EPMC3837481 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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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.

Chandrasekharan Unni M UM Dechert Lisa L Davidson Uchechukwu I UI Waitkus Matthew M Mavrakis Lori L Lyons Katherine K Beach Jordan R JR Li Xiaoxia X Egelhoff Thomas T TT Fox Paul L PL DiCorleto Paul E PE

Science signaling 20130716 284

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 ...[more]

PMID: 23861542

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Project description:The molecular mechanisms underlying larval shell development in mollusks remain largely elusive. We previously found evident filamentous actin (F-actin) aggregations in the developing shell field of the patellogastropod Lottia goshimai, indicating roles of actomyosin networks in the process. In the present study, we functionally characterized nonmuscle myosin II (NM II), the key molecule in actomyosin networks, in the larval shell development of L. goshimai. Immunostaining revealed general colocalization of phosphorylated NM II and F-actin in the shell field. When inhibiting the phosphorylation of NM II using the specific inhibitor blebbistatin in one- or 2-h periods during shell field morphogenesis (6-8 h post-fertilization, hpf), the larval shell plate was completely lost in the veliger larva (24 hpf). Scanning electron microscopy revealed that the nascent larval shell plate could not be developed in the manipulated larvae (10 hpf). Further investigations revealed that key events in shell field morphogenesis were inhibited by blebbistatin pulses, including invagination of the shell field and cell shape changes and cell rearrangements during shell field morphogenesis. These factors caused the changed morphology of the shell field, despite the roughly retained "rosette" organization. To explore whether the specification of related cells was affected by blebbistatin treatments, we investigated the expression of four potential shell formation genes (bmp2/4, gata2/3, hox1 and engrailed). The four genes did not show evident changes in expression level, indicating unaffected cell specification in the shell field, while the gene expression patterns showed variations according to the altered morphology of the shell field. Together, our results reveal that NM II contributes to the morphogenesis of the shell field and is crucial for the formation of the larval shell plate in L. goshimai. These results add to the knowledge of the mechanisms of molluskan shell development.

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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.

Publications

Release of nonmuscle myosin II from the cytosolic domain of tumor necrosis factor receptor 2 is required for target gene expression.

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