title: The Smurf ubiquitin ligases regulate tissue separation via antagonistic interactions with ephrinB1.
abstract: The formation of tissue boundaries is dependent on the cell-cell adhesion/repulsion system that is required for normal morphogenetic processes during development. The Smad ubiquitin regulatory factors (Smurfs) are E3 ubiquitin ligases with established roles in cell growth and differentiation, but whose roles in regulating cell adhesion and migration are just beginning to emerge. Here, we demonstrate that the Smurfs regulate tissue separation at mesoderm/ectoderm boundaries through antagonistic interactions with ephrinB1, an Eph receptor ligand that has a key role in regulating the separation of embryonic germ layers. EphrinB1 is targeted by Smurf2 for degradation; however, a Smurf1 interaction with ephrinB1 prevents the association with Smurf2 and precludes ephrinB1 from ubiquitination and degradation, since it is a substantially weaker substrate for Smurf1. Inhibition of Smurf1 expression in embryonic mesoderm results in loss of ephrinB1-mediated separation of this tissue from the ectoderm, which can be rescued by the coincident inhibition of Smurf2 expression. This system of differential interactions between Smurfs and ephrinB1 regulates the maintenance of tissue boundaries through the control of ephrinB protein levels.
authors.affiliation: Laboratory of Cell and Developmental Signaling, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
authors.forename: Yoo-Seok
authors.initials: YS
authors.lastname: Hwang
authors.forename: Hyun-Shik
authors.initials: HS
authors.lastname: Lee
authors.forename: Teddy
authors.initials: T
authors.lastname: Kamata
authors.forename: Kathleen
authors.initials: K
authors.lastname: Mood
authors.forename: Hee Jun
authors.initials: HJ
authors.lastname: Cho
authors.forename: Emily
authors.initials: E
authors.lastname: Winterbottom
authors.forename: Yon Ju
authors.initials: YJ
authors.lastname: Ji
authors.forename: Arvinder
authors.initials: A
authors.lastname: Singh
authors.forename: Ira O
authors.initials: IO
authors.lastname: Daar
mesh_terms: D000818:Animals; D004625:Embryo, Nonmammalian / Q000201:enzymology; D036387:Ephrin-B1 / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus / Q000235:genetics* / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D036387:Ephrin-B1; D029961:Zebrafish Proteins; D044767:Ubiquitin-Protein Ligases; D020559:Monomeric GTP-Binding Proteins; C549425:rhoab protein, zebrafish