Endosomal Sorting of Notch Receptors Through COMMD9-dependent Pathways Modulates Notch Signaling

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2015 Nov 11

PMID 26553930

Citations 28

Authors

Haiying Li

Yeon Koo

Xicheng Mao

Luis Sifuentes-Dominguez

Lindsey L Morris

Da Jia

Naoteru Miyata

Rebecca A Faulkner

Jan M van Deursen

Marc Vooijs

Daniel D Billadeau

Bart van de Sluis

Ondine Cleaver

Ezra Burstein

Affiliations

Soon will be listed here.

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.

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