Jin Jiang

..Taken together, these results suggest that Cul3 downregulates Ci levels to modulate Hh signaling activity, thus ensuring proper cell proliferation during retinal development...

..Tissue- and developmental stage-specific expression of HIB and its homologs in vertebrates may provide a conserved mechanism for ensuring precision in spatial and temporal control of Hh signaling...

..We propose that phosphorylation of Ci by CKI creates multiple Slimb/beta-TRCP binding sites that act cooperatively to recruit SCF(Slimb/beta-TRCP)...

..Our data indicate that Hh induces progressive Smo phosphorylation by PKA and CKI, leading to elevation of Smo cell-surface levels and signalling activity...

..We discuss how the Hh pathway has diverged during evolution and how it integrates with other signaling pathways to control cell growth and patterning...

..Taken together, our results suggest that Smo transduces the Hh signal by physically interacting with the Cos2/Fu protein complex...

..dMST forms a complex with Sav and Wts, two tumor suppressors also implicated in regulating both cell proliferation and apoptosis, suggesting that they act in common pathways...

..We propose that Cos2 recruits multiple kinases to efficiently phosphorylate Ci and that Hh inhibits Ci phosphorylation by specifically interfering with kinase recruitment...

..We provide evidence that HIB prevents aberrant Hh signaling posterior to the morphogenic furrow, which is essential for normal eye development...

..Finally, we provide evidence that several CKI isoforms including CKIalpha and Gish/CKIgamma can phosphorylate the Wg coreceptor Arrow (Arr), which may account, at least in part, for their positive roles in the Wg pathway...

..Finally, Sd recruits Yki to the enhancer of the pathway-responsive gene diap1, suggesting that diap1 is a direct transcriptional target of the Hpo pathway...

..We propose that Sgg/GSK3 acts in conjunction with PKA to cause hyperphosphorylation of Ci, which targets it for proteolytic processing, and that Hh opposes Ci proteolysis by promoting its dephosphorylation...

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..Finally, we provided evidence that Hpo signaling restricted Yki nuclear localization depending on CRM1-mediated nuclear export...

..We discuss how Smo conformational change regulates the intracellular signaling complex and how Smo transduces the graded Hh signaling activities through different conformational states...

..Finally, we show that the Hpo pathway mediator Yorkie (Yki) is also required in precursor cells for injury-induced ISC proliferation in response to tissue-damaging reagent DSS...

..Hence, by employing multiple Arg clusters as inhibitory elements counteracted by differential phosphorylation, SMO acts as a rheostat to translate graded HH signals into distinct responses...

..In addition, we find that adding a nuclear localization signal (NLS) to exposed regions of Ci155 greatly facilitates its nuclear translocation, suggesting that the cytoplasmic retention of Ci155 may also depend on NLS masking...

..Overexpression of Sav or dimerized Ed cytoplasmic domain suppressed loss-of-Ed phenotypes. We propose that Ed may link cell-cell contact to Hpo signaling through binding and stabilizing Sav, thus modulating the Hpo kinase activity...

..Thus, Gprk2 forms a positive feedback loop and acts downstream from PKA and CK1 to facilitate high-level Hh signaling by promoting the active state of Smo through direct phosphorylation and molecular scaffolding...

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..Our results provide a mechanistic insight into how HIB/SPOP recognizes its substrates and have important implications for the genome-wide prediction of substrates for Cul3-based E3 ligases...

..Hence, despite divergence in their primary sequences and their subcellular trafficking, mSmo and dSmo employ analogous mechanisms for their activation...

..TNF-alpha increases cell death by approximately 2-fold, which is attenuated by both EMD and TGF-beta1. CONCLUSION: Like TGF-beta1, EMD protects osteoblasts from inflammation-induced apoptosis...

..Together, these findings define a pathway for plexin signaling and provide insights into the mechanism for semaphorin-induced activation of plexins...

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..The sequential and regulated proteolysis by γ-secretase and MIPEP suggests a new means by which Notch function can be modulated...

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..CONCLUSION: This study suggests that direct contact between EMD and osteoblasts is not required to induce cell proliferation. Soluble peptides released from EMD may contribute to the stimulating effects of EMD on cell proliferation...

..Our findings suggest that hyperphosphorylated Per is targeted to the proteasome by interactions with Slimb...

..Other missense mutations map to amino acids that are conserved among Fringe proteins, but not among other glycosyltransferases, and thus may identify structural motifs that are required for unique aspects of Fringe activity...

..Our data suggest that Cos2-Smo interaction blocks Hh-induced Smo phosphorylation, and that Fu promotes Smo phosphorylation by antagonizing Cos2...

..Thus, these results together demonstrate that WntD is regulated by the Dorsal/Twist/Snail network, and is an inhibitor of Dorsal nuclear localization and function...

..CONCLUSIONS: EMD promotes both proliferation and differentiation of MC3T3-E1 cells and indirectly inhibits osteoclastogenesis and osteoclast function by stimulating the expression of OPG...

..Thus, broad overexpression of IGF-I in cells of the osteoblast lineage increased indices of bone formation and resorption...

..As unconstrained elevation of Smo activity contributes to many human cancers including skin, lung, pancreas, and prostate cancers, our study may provide new avenues for improving diagnosis and therapeutics of these cancers. ..

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..Hence, understanding the Hh signaling mechanisms, as proposed by this project, may provide new avenues for improving diagnosis and therapeutics of cancer. ..

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..Knowledge gained from the proposed study may provide new avenues for diagnosis and therapeutic intervention of cancers caused by mis-regulation of Hh signaling activity. ..

..These studies could lead to the development of new, specific, bone active pharmaceuticals with the potential to improve dental health. ..

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