Frizzled/planar cell polarity (PCP) signaling regulates cell motility in several tissues, including ommatidial rotation in Drosophila melanogaster. The Nemo kinase has also been linked to cell motility regulation and ommatidial rotation. The mechanistic role(s) of Nemo during rotation remain however obscure. We demonstrate that nemo functions throughout the entire rotation movement promoting rate of rotation. Genetic and molecular studies indicate that Nemo binds both the core PCP factor complex of Strabismus–Prickle, and the E-cadherin–β-catenin (Armadillo) complex, which colocalize and like Nemo also promote rotation. Strabismus/Vang binds and stabilizes Nemo asymmetrically within the ommatidial precluster. Nemo and β-catenin then act synergistically promoting rotation, which is mediated in vivo through Nemo phosphorylation of β-catenin. Our data suggest that Nemo serves as a conserved molecular link between core PCP factors and E-cad/β-catenin complexes, promoting ommatidial rotation and cell motility in general.

Drosophila Nemo is the founding member of the Nemo-like kinase (Nlk) family of serine/threonine protein kinases that are involved in several Wnt signal transduction pathways. Here we report a novel function for Nemo in the inhibition of bone morphogenetic protein (BMP) signaling. Genetic interaction studies demonstrate that nemo can antagonize BMP signaling and can inhibit the expression of BMP target genes during wing development. Nemo can bind to and phosphorylate the BMP effector Mad. In cell culture, phosphorylation by Nemo blocks the nuclear accumulation of Mad by promoting export of Mad from the nucleus in a kinase-dependent manner. This is the first example of the inhibition of Drosophila BMP signaling by a MAPK and represents a novel mechanism of Smad inhibition through the phosphorylation of a conserved serine residue within the MH1 domain of Mad.

Precisely regulated signal transduction pathways are crucial for the regulation of developmental events and prevention of tumorigenesis. Both the Transforming Growth Factor β (TGFβ)/Bone morphogenetic protein (BMP) and Wnt/Wingless (Wg) pathways play essential roles in organismal patterning and growth, and their deregulation can lead to cancers. We describe a mechanism of interaction between Drosophila Wg and BMP signaling in which Wg target gene expression is antagonized by BMP signaling. In vivo, high levels of both an activated BMP receptor and the BMP effector Mad can inhibit the expression of Wg target genes. Conversely, loss of mad can induce Wg target gene expression. In addition, we find that ectopic expression in vivo of the Wg transcription factor dTcf is able to suppress the inhibitory effect caused by ectopic Mad. In vitro binding studies revealed competition for dTcf binding between Mad and the Wnt effector β-catenin/Armadillo (Arm). Our in vivo genetic analyses and target gene studies support a mechanism consistent with the in vitro binding and competition studies, namely that BMP pathway components can repress Wg target gene expression by influencing the binding of Arm and dTcf.

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The immunotoxic effects of the isoquinoline alkaloid berberine (BBR) were investigated in Balb/c mice. Here, BBR was administered daily by intraperitoneal injection at doses of 5 and 10 mg/kg for 14 days. Following the exposure, host spleen weight, cellularity and histopathology, as well as delayed-type hypersensitivity (DTH) responses, hemagglutination titers (HA), spleen cell subtype profiles, splenocyte cytokine production and lymphocyte proliferation were studied in all of the test groups of animals. The results showed that the high dose of BBR (10 mg/kg) could suppress both cellular and humoral immune functions in the treated hosts. BBR at 5 mg/kg only appeared to impact on DTH responses and lymphoproliferation. Based on the finding here, it would seem that BBR has effective immunosuppressive properties. Mechanistic studies are required to determine exactly how this material is acting to impart many of the immunotoxic effects demonstrated here. At the same time, further research should also be performed on BBR to further develop its potential use as an effective immunosuppressant or co-adjuvant for the treatment of diseases caused by an exaggerated or unwanted immune response.