title: Endosomal sorting of Notch receptors through COMMD9-dependent pathways modulates Notch signaling.
abstract: Notch family members are transmembrane receptors that mediate essential developmental programs. Upon ligand binding, a proteolytic event releases the intracellular domain of Notch, which translocates to the nucleus to regulate gene transcription. In addition, Notch trafficking across the endolysosomal system is critical in its regulation. In this study we report that Notch recycling to the cell surface is dependent on the COMMD-CCDC22-CCDC93 (CCC) complex, a recently identified regulator of endosomal trafficking. Disruption in this system leads to intracellular accumulation of Notch2 and concomitant reduction in Notch signaling. Interestingly, among the 10 copper metabolism MURR1 domain containing (COMMD) family members that can associate with the CCC complex, only COMMD9 and its binding partner, COMMD5, have substantial effects on Notch. Furthermore, Commd9 deletion in mice leads to embryonic lethality and complex cardiovascular alterations that bear hallmarks of Notch deficiency. Altogether, these studies highlight that the CCC complex controls Notch activation by modulating its intracellular trafficking and demonstrate cargo-specific effects for members of the COMMD protein family.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Haiying
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Yeon
authors.initials: Y
authors.lastname: Koo
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Xicheng
authors.initials: X
authors.lastname: Mao
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Luis
authors.initials: L
authors.lastname: Sifuentes-Dominguez
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Lindsey L
authors.initials: LL
authors.lastname: Morris
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Da
authors.initials: D
authors.lastname: Jia
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Naoteru
authors.initials: N
authors.lastname: Miyata
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Faulkner
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Jan M
authors.initials: JM
authors.lastname: van Deursen
authors.affiliation: Department of Radiotherapy (MAASTRO)/GROW-School for Developmental Biology and Oncology, Maastricht University, 6229 ER Maastricht, Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: Vooijs
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905 Department of Immunology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.affiliation: Molecular Genetics Section - Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: van de Sluis
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Ondine
authors.initials: O
authors.lastname: Cleaver
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390 ezra.burstein@utsouthwestern.edu.
authors.forename: Ezra
authors.initials: E
authors.lastname: Burstein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D021381:Protein Transport / Q000502:physiology*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D051880:Receptors, Notch