Toward a systems-level understanding of the Hedgehog signaling pathway: defining the complex, robust, and fragile
ABSTRACT The Hedgehog (Hh) signaling pathway plays a fundamental role in development and tissue homeostasis, governing cell proliferation and differentiation, as well as cell fate. Hh signaling is mediated by an intricate network of proteins that have positive and negative roles that work in concert to fine-tune signaling output. Using feedback loops, redundancy and subcellular compartmentalization, the temporal and spatial dynamics of Hh signaling have evolved to be complex and robust. Yet developmental defects and cancers that arise from perturbation of the Hh pathway reflect specific pathway fragilities. Importantly, these fragile nodes and edges present opportunities for the design of targeted therapies. Despite these significant advances, unconnected molecular links within the Hh pathway still remain, many of which revolve around the dependence of Hh signaling on the primary cilium, an antenna-like sensory organelle. A systems-level understanding of Hh signaling and of ciliary biology will comprehensively define all nodes and edges of the Hh signaling network and will help identify precise therapeutic targets. WIREs Syst Biol Med 2012. doi: 10.1002/wsbm.1193 For further resources related to this article, please visit the WIREs website.
- SourceAvailable from: Jose Sergio Hleap[Show abstract] [Hide abstract]
ABSTRACT: Assessing protein modularity is important to understand protein evolution. Still the question of the existence of a sub-domain modular architecture remains. We propose a graph-theory approach with significance and power testing to identify modules in protein structures. In the first step, clusters are determined by optimizing the partition that maximizes the modularity score. Second, each cluster is tested for significance. Significant clusters are referred to as modules. Evolutionary modules are identified by analyzing homologous structures. Dynamic modules are inferred from sets of snapshots of molecular simulations. We present here a methodology to identify sub-domain architecture robustly, biologically meaningful, and statistically supported. The robustness of this new method is tested using simulated data with known modularity. Modules are correctly identified even when there is a low correlation between landmarks within a module. We also analyzed the evolutionary modularity of a data set of ¿-amylase catalytic domain homologs, and the dynamic modularity of the Niemann-Pick C1 (NPC1) protein N-terminal domain. The ¿-amylase contains an (¿/ß)8 barrel (TIM barrel) with the polysaccharides cleavage site and a calcium-binding domain. In this data set we identified four robust evolutionary modules, one of which forms the minimal functional TIM barrel topology. The NPC1 protein is involved in the intracellular lipid metabolism coordinating sterol trafficking. NPC1 N-terminus is the first luminal domain which binds to cholesterol and its oxygenated derivatives. Our inferred dynamic modules in the protein NPC1 are also shown to match functional components of the protein related to the NPC1 disease. A domain compartmentalization can be found and described in correlation space. To our knowledge, there is no other method attempting to identify sub-domain architecture from the correlation among residues. Most attempts made focus on sequence motifs of protein-protein interactions, binding sites, or sequence conservancy. We were able to describe functional/structural sub-domain architecture related to key residues for starch cleavage, calcium, and chloride binding sites in the ¿-amylase, and sterol opening-defining modules and disease-related residues in the NPC1. We also described the evolutionary sub-domain architecture of the ¿-amylase catalytic domain, identifying the already reported minimum functional TIM barrel.BMC Structural Biology 10/2013; 13(1):20. DOI:10.1186/1472-6807-13-20 · 2.22 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Diphospho-myo-inositol polyphosphates have many roles to play including roles in apoptosis, vesicle trafficking, the response of cells to stress, the regulation of telomere length and DNA damage repair, and inhibition of the cyclin-dependent kinase Pho85 system that monitors phosphate levels. This review focuses on the three classes of enzymes involved in the metabolism of these compounds - inositol hexakisphosphate kinases (IP6K), inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinases (PPIP5K), and diphosphoinositol polyphosphate phosphohydrolases (DIPP). However, these enzymes have roles beyond being mere catalysts, and their interactions with other proteins have cellular consequences. Through their interactions the three inositol hexakisphosphate kinases have roles in exocytosis, diabetes, the response to infection, and apoptosis. The two inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinases influence the cellular response to phosphatidylinositol (3,4,5)-trisphosphate and the migration of pleckstrin homology domain-containing proteins to the plasma membrane. The five diphosphoinositol polyphosphate phosphohydrolases interact with ribosomal proteins and transcription factors, and proteins involved in membrane trafficking, exocytosis, ubiquitination and the proteasomal degradation of target proteins. Possible directions for future research to further elucidate the roles of these enzymes are highlighted. This article is protected by copyright. All rights reserved.FEBS Journal 10/2013; DOI:10.1111/febs.12575 · 3.99 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Renal cystic diseases are a leading cause of renal failure. Mutations associated with renal cystic diseases reside in genes encoding proteins that localize to primary cilia. These cystoproteins can disrupt ciliary structure or cilia-mediated signaling, although molecular mechanisms connecting cilia function to renal cystogenesis remain unclear. The ciliary gene, Thm1(Ttc21b), negatively regulates Hedgehog signaling and is most commonly mutated in ciliopathies. We report that loss of murine Thm1 causes cystic kidney disease, with persistent proliferation of renal cells, elevated cAMP levels, and enhanced expression of Hedgehog signaling genes. Notably, the cAMP-mediated cystogenic potential of Thm1-null kidney explants was reduced by genetically deleting Gli2, a major transcriptional activator of the Hedgehog pathway, or by culturing with small molecule Hedgehog inhibitors. These Hedgehog inhibitors acted independently of protein kinase A and Wnt inhibitors. Furthermore, simultaneous deletion of Gli2 attenuated the renal cystic disease associated with deletion of Thm1. Finally, transcripts of Hedgehog target genes increased in cystic kidneys of two other orthologous mouse mutants, jck and Pkd1, and Hedgehog inhibitors reduced cystogenesis in jck and Pkd1 cultured kidneys. Thus, enhanced Hedgehog activity may have a general role in renal cystogenesis and thereby present a novel therapeutic target.Journal of the American Society of Nephrology 04/2014; 25(10). DOI:10.1681/ASN.2013070735 · 9.47 Impact Factor