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1.
Proc Natl Acad Sci U S A ; 111(7): 2578-83, 2014 Feb 18.
Article in English | MEDLINE | ID: mdl-24550286

ABSTRACT

The transforming growth factor ß (TGFß) superfamily of signaling pathways, including the bone morphogenetic protein (BMP) subfamily of ligands and receptors, controls a myriad of developmental processes across metazoan biology. Transport of the receptors from the plasma membrane to endosomes has been proposed to promote TGFß signal transduction and shape BMP-signaling gradients throughout development. However, how postendocytic trafficking of BMP receptors contributes to the regulation of signal transduction has remained enigmatic. Here we report that the intracellular domain of Caenorhabditis elegans BMP type I receptor SMA-6 (small-6) binds to the retromer complex, and in retromer mutants, SMA-6 is degraded because of its missorting to lysosomes. Surprisingly, we find that the type II BMP receptor, DAF-4 (dauer formation-defective-4), is retromer-independent and recycles via a distinct pathway mediated by ARF-6 (ADP-ribosylation factor-6). Importantly, we find that loss of retromer blocks BMP signaling in multiple tissues. Taken together, our results indicate a mechanism that separates the type I and type II receptors during receptor recycling, potentially terminating signaling while preserving both receptors for further rounds of activation.


Subject(s)
Bone Morphogenetic Protein Receptors, Type I/metabolism , Bone Morphogenetic Proteins/metabolism , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/physiology , Multiprotein Complexes/metabolism , Receptors, Cell Surface/metabolism , Receptors, Transforming Growth Factor beta/metabolism , Signal Transduction/physiology , Animals , Animals, Genetically Modified , Caenorhabditis elegans/metabolism , Microscopy, Fluorescence , Multiprotein Complexes/genetics , Real-Time Polymerase Chain Reaction , Recombinant Fusion Proteins/metabolism , Signal Transduction/genetics
2.
Mol Syst Biol ; 9: 652, 2013.
Article in English | MEDLINE | ID: mdl-23549480

ABSTRACT

Src homology 3 (SH3) domains bind peptides to mediate protein-protein interactions that assemble and regulate dynamic biological processes. We surveyed the repertoire of SH3 binding specificity using peptide phage display in a metazoan, the worm Caenorhabditis elegans, and discovered that it structurally mirrors that of the budding yeast Saccharomyces cerevisiae. We then mapped the worm SH3 interactome using stringent yeast two-hybrid and compared it with the equivalent map for yeast. We found that the worm SH3 interactome resembles the analogous yeast network because it is significantly enriched for proteins with roles in endocytosis. Nevertheless, orthologous SH3 domain-mediated interactions are highly rewired. Our results suggest a model of network evolution where general function of the SH3 domain network is conserved over its specific form.


Subject(s)
Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/metabolism , src Homology Domains/genetics , Amino Acid Sequence , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/genetics , Conserved Sequence , Endocytosis/genetics , Evolution, Molecular , Molecular Sequence Data , Protein Interaction Mapping , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Structural Homology, Protein , Two-Hybrid System Techniques
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