title: β-Integrin de-phosphorylation by the Density-Enhanced Phosphatase DEP-1 attenuates EGFR signaling in C. elegans.
abstract: Density-Enhanced Phosphatase-1 (DEP-1) de-phosphorylates various growth factor receptors and adhesion proteins to regulate cell proliferation, adhesion and migration. Moreover, dep-1/scc1 mutations have been detected in various types of human cancers, indicating a broad tumor suppressor activity. During C. elegans development, DEP-1 mediates binary cell fate decisions by negatively regulating EGFR signaling. Using a substrate-trapping DEP-1 mutant in a proteomics approach, we have identified the C. elegans β-integrin subunit PAT-3 as a specific DEP-1 substrate. DEP-1 selectively de-phosphorylates tyrosine 792 in the membrane-proximal NPXY motif to promote integrin activation via talin recruitment. The non-phosphorylatable β-integrin mutant pat-3(Y792F) partially suppresses the hyperactive EGFR signaling phenotype caused by loss of dep-1 function. Thus, DEP-1 attenuates EGFR signaling in part by de-phosphorylating Y792 in the β-integrin cytoplasmic tail, besides the direct de-phosphorylation of the EGFR. Furthermore, in vivo FRAP analysis indicates that the αβ-integrin/talin complex attenuates EGFR signaling by restricting receptor mobility on the basolateral plasma membrane. We propose that DEP-1 regulates EGFR signaling via two parallel mechanisms, by direct receptor de-phosphorylation and by restricting receptor mobility through αβ-integrin activation.
authors.affiliation: Institute of Molecular Life Sciences, University of Zürich, Winterthurerstr. 190, University of Zürich, Zürich, Switzerland.|Molecular Life Science Zürich PhD program, Zürich, Switzerland.
authors.forename: Michael
authors.identifier: 0000-0003-3506-4621
authors.initials: M
authors.lastname: Walser
authors.affiliation: Institute of Molecular Life Sciences, University of Zürich, Winterthurerstr. 190, University of Zürich, Zürich, Switzerland.
authors.forename: Christoph Alois
authors.initials: CA
authors.lastname: Umbricht
authors.affiliation: Institute of Molecular Life Sciences, University of Zürich, Winterthurerstr. 190, University of Zürich, Zürich, Switzerland.
authors.forename: Erika
authors.initials: E
authors.lastname: Fröhli
authors.affiliation: Functional Genomics Center Zürich, University of Zürich/ETH Zürich, Winterthurerstr. 190, Zürich, Switzerland.
authors.forename: Paolo
authors.identifier: 0000-0001-8429-3557
authors.initials: P
authors.lastname: Nanni
authors.affiliation: Institute of Molecular Life Sciences, University of Zürich, Winterthurerstr. 190, University of Zürich, Zürich, Switzerland.
authors.forename: Alex
authors.identifier: 0000-0002-4098-3721
authors.initials: A
authors.lastname: Hajnal
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D039641:Integrin beta Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D029742:Caenorhabditis elegans Proteins; D039641:Integrin beta Chains; C093515:pat-3 protein, C elegans; D066246:ErbB Receptors; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3