Drosophila JUN relays the JUN amino-terminal kinase signal transduction pathway to the Decapentaplegic signal transduction pathway in regulating epithelial cell sheet movement

ABSTRACT The Drosophila melanogaster JUN N-terminal kinase (DJNK) and DPP (decapentaplegic) signal transduction pathways coordinately regulate epithelial cell sheet movement during the process of dorsal closure in the embryo. By a genetic screen of mutations affecting dorsal closure in Drosophila, we have now identified a multidomain protein, connector of kinase to AP-1 (cka), that functions in the DJNK pathway and controls the localized expression of dpp in the leading-edge cells. We have also investigated how CKA acts. This unique molecule forms a complex with HEP (DJNKK), BSK (DJNK), DJUN, and DFOS. Complex formation activates BSK kinase, which in turn phosphorylates and activates DJUN and DFOS. These data suggest that CKA represents a novel molecule regulating AP-1 activity by organizing a molecular complex of kinases and transcription factors, thus coordinating the spatial-temporal expression of AP-1-regulated genes.

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rac1 regulates a cytokine-stimulated, redox-dependent pathway necessary for NF-kappaB activation.

Molecular and Cellular Biology ◽

10.1128/mcb.16.12.7115 ◽

1996 ◽

Vol 16 (12) ◽

pp. 7115-7121 ◽

Cited By ~ 240

Author(s):

D J Sulciner ◽

K Irani ◽

Z X Yu ◽

V J Ferrans ◽

P Goldschmidt-Clermont ◽

...

Keyword(s):

Signal Transduction ◽

Hela Cells ◽

Recombinant Adenovirus ◽

Signal Transduction Pathway ◽

Nuclear Extract ◽

Dominant Negative ◽

Transduction Pathway ◽

Amino Terminal ◽

Dependent Signal ◽

Nf Kappab

The signal transduction pathway leading to the activation of the transcription factor NF-kappaB remains incompletely characterized. We demonstrate that in HeLa cells, transient expression of a constitutively active mutant of the small GTP-binding protein rac1 (V12rac1) leads to a significant increase in NF-kappaB transcriptional activity. In addition, expression of a dominant-negative rac1 mutant (N17rac1) inhibits basal and interleukin 1beta-stimulated NF-kappaB activity. Gel shift analysis using nuclear extract prepared from HeLa cells infected with a recombinant adenovirus encoding N17rac1 (Ad.N17racl) showed reduced levels of cytokine-stimulated DNA binding to a consensus NF-kappaB binding site. We demonstrate that rac proteins function downstream of ras proteins in the activation of NF-kappaB. In addition, V12rac1 stimulation of NF-kappaB activity is shown to be independent of the ability of rac proteins to activate the family of c-jun amino-terminal kinases. In an effort to further explore how rac proteins might regulate NF-kappaB activity, we demonstrate that expression of V12rac1 in HeLa cells or stimulation with cytokine results in a significant increase in intracellular reactive oxygen species (ROS). Treatment of cells with either of two chemically unrelated antioxidants inhibits the rise in ROS that occurs following V12rac1 expression as well as the ability of V12rac1 to stimulate NF-kappaB activity. These results suggest that in HeLa cells, rac1 regulates intracellular ROS production and that rac proteins function as part of a redox-dependent signal transduction pathway leading to NF-kappaB activation.

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