\u3cem\u3eDrosophila Unpaired\u3c/em\u3e Encodes a Secreted Protein that Activates the JAK Signaling Pathway

In vertebrates, many cytokines and growth factors have been identified as activators of the JAK/STAT signaling pathway. In Drosophila, JAK and STAT molecules have been isolated, but no ligands or receptors capable of activating the pathway have been described. We have characterized the unpaired (upd) gene, which displays the same distinctive embryonic mutant defects as mutations in the Drosophila JAK (hopscotch) and STAT (stat92E) genes. Upd is a secreted protein, associated with the extracellular matrix, that activates the JAK pathway. We propose that Upd is a ligand that relies on JAK signaling to stimulate transcription of pair-rule genes in a segmentally restricted manner in the early Drosophila embryo

Monoclonal Antibody to a 35 kD Epidermal Protein Induces Cell Detachment

A murine monoclonal antibody (ECS-1) was prepared from BALB/c mice immunized with trypsinized cultured human foreskin keratinocytes. The antibody showed a pattern suggestive of intercellular staining on the nucleated layers of normal human epidermis, adult palm, mouse lip epidermis, and cultured human keratinocytes. ECS-1 stained human fetal skin by 9 weeks estimated gestational age. ECS-1 reacted with a 35 kD protein extracted from neonatal foreskin epidermis and cultured human keratinocytes. The protein required Nonidet P-40 or sodium dodecyl sulfate and mercaptoethanol for solubilization. ECS-1 induced epidermal cell detachment which was enhanced by complement. ECS- 1 shares characteristics with human pemphigus antibodies

Sea Urchin FGFR Muscle-Specific Expression: Posttranscriptional Regulation in Embryos and Adults

AbstractWe have shown previously byin situhybridization that a gene encoding a fibroblast growth factor receptor (SpFGFR) is transcribed in many cell types during the initial phases of sea urchin embryogenesis (Strongylocentrotus purpuratus) (McCoonet al., J. Biol. Chem. 271,20119–20195, 1996). Here we demonstrate by immunostaining with affinity-purified antibody that SpFGFR protein is detectable only in muscle cells of the embryo and appears at a time suggesting that its function is not in commitment to a muscle fate, but instead may be required to support the proliferation, migration, and/or differentiation of myoblasts. Surprisingly, we find thatSpFGFRtranscripts are enriched in embryo nuclei, suggesting that lack of processing and/or cytoplasmic transport in nonmuscle cells is at least part of the posttranscriptional regulatory mechanism. Western blots show that SpFGFR is also specifically expressed in adult lantern muscle, but is not detectable in other smooth muscle-containing tissues, including tube foot and intestine, or in coelomocytes, despite the presence ofSpFGFRtranscripts at similar concentrations in all these tissues. We conclude that in both embryos and adults, muscle-specific SpFGF receptor synthesis is controlled primarily at a posttranscriptional level. We show by RNase protection assays that transcripts encoding the IgS variant of the ligand binding domain of the receptor, previously shown to be enriched in embryo endomesoderm fractions, are the predominant, if not exclusive,SpFGFRtranscripts in lantern muscle. Together, these results suggest that only a minority ofSpFGFRtranscripts are processed, exported, and translated in both adult and embryonic muscle cells and these contain predominantly, if not exclusively, IgS ligand binding domain sequences

Drosophila unpaired encodes a secreted protein that activates the JAK signaling pathway

In vertebrates, many cytokines and growth factors have been identified as activators of the JAK/STAT signaling pathway. In Drosophila, JAK and STAT molecules have been isolated, but no ligands or receptors capable of activating the pathway have been described. We have characterized the unpaired (upd) gene, which displays the same distinctive embryonic mutant defects as mutations in the Drosophila JAK (hopscotch) and STAT (stat92E) genes. Upd is a secreted protein, associated with the extracellular matrix, that activates the JAK pathway. We propose that Upd is a ligand that relies on JAK signaling to stimulate transcription of pair-rule genes in a segmentally restricted manner in the early Drosophila embryo

Antibody-mediated blockade of integrin ?v?6 inhibits tumor progression in vivo by a transforming growth factor-?–regulated mechanism

The ?v?6 integrin is up-regulated on epithelial malignancies and has been implicated in various aspects of cancer progression. Immunohistochemical analysis of ?v?6 expression in 10 human tumor types showed increased expression relative to normal tissues. Squamous carcinomas of the cervix, skin, esophagus, and head and neck exhibited the highest frequency of expression, with positive immunostaining in 92% (n = 46), 84% (n = 49), 68% (n = 56), and 64% (n = 100) of cases, respectively. We studied the role of ?v?6 in Detroit 562 human pharyngeal carcinoma cells in vitro and in vivo. Prominent ?v?6 expression was detected on tumor xenografts at the tumor-stroma interface resembling the expression on human head and neck carcinomas. Nonetheless, coculturing cells in vitro with matrix proteins did not up-regulate ?v?6 expression. Detroit 562 cells showed ?v?6-dependent adhesion and activation of transforming growth factor-? (TGF-?) that was inhibited >90% with an ?v?6 blocking antibody, 6.3G9. Although both recombinant soluble TGF-? receptor type-II (rsTGF-?RII-Fc) and 6.3G9 inhibited TGF-?–mediated Smad2/3 phosphorylation in vitro, there was no effect on proliferation. Conversely, in vivo, 6.3G9 and rsTGF-?RII-Fc inhibited xenograft tumor growth by 50% (n = 10, P < 0.05) and >90% (n = 10, P < 0.001), respectively, suggesting a role for the microenvironment in this response. However, stromal collagen and smooth muscle actin content in xenograft sections were unchanged with treatments. Although further studies are required to consolidate in vitro and in vivo results and define the mechanisms of tumor inhibition by ?v?6 antibodies, our findings support a role for ?v?6 in human cancer and underscore the therapeutic potential of function blocking ?v?6 antibodies