TY - JOUR
T1 - Endosomal sorting of notch receptors through COM MD9-dependent pathways modulates notch signaling
AU - Li, Haiying
AU - Koo, Yeon
AU - Mao, Xicheng
AU - Sifuentes-Dominguez, Luis
AU - Morris, Lindsey L.
AU - Jia, Da
AU - Miyata, Naoteru
AU - Faulkner, Rebecca A.
AU - van Deursen, Jan M.
AU - Vooijs, Marc
AU - Billadeau, Daniel D.
AU - Van de Sluis, Bart
AU - Cleaver, Ondine
AU - Burstein, Ezra
N1 - Funding Information:
The work of E. Burstein is supported by National Institutes of Health (R01DK073639 and R56AI113274) and CPRIT (RP130409). The work of D.D. Billadeau is supported by National Institutes of Health (grant AI065474). The work of B. van de Sluis is supported by the Netherlands Organization for Scientific Research (NWO-ALW grant 817.02.022).
Funding Information:
We are grateful to several investigators that provided critical reagents for our studies, including Eric Olson, Rhonda Bassel-Duby (Nkx2.5-Cre mice), Masashi Yanagisawa (Tie2-Cre mice), Hiromi Yanagisawa (Sm22-Cre mice), Lawrence Lum (reporter plasmids), and Spyros Artavanis-Tsakonas (Notch2 expression vector). We are also grateful to Eric Olson, Rhonda Basel-Duby, and Doug Engel for their generous help with some of the early embryologic studies. In addition, we are indebted to James Richardson, John Shelton, and the staff of the Molecular Pathology Core for their assistance with several aspects of this study. We are also grateful to the personnel and facilities of the Live Cell Imaging Core at University of Texas Southwestern. The work of E. Burstein is supported by National Institutes of Health (R01DK073639 and R56AI113274) and CPR IT (RP130409). The work of D.D. Billadeau is supported by National Institutes of Health (grant AI065474). The work of B. van de Sluis is supported by the Netherlands Organization for Scientific Research (NWO-ALW grant 817.02.022).
Publisher Copyright:
© 2015 Schreiber et al.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - 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 COM MD-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 (COM MD) family members that can associate with the CCC complex, only COM MD9 and its binding partner, COM MD5, 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 COM MD protein family.
AB - 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 COM MD-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 (COM MD) family members that can associate with the CCC complex, only COM MD9 and its binding partner, COM MD5, 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 COM MD protein family.
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U2 - 10.1083/jcb.201505108
DO - 10.1083/jcb.201505108
M3 - Article
C2 - 26553930
AN - SCOPUS:84980332364
SN - 0021-9525
VL - 211
SP - 605
EP - 617
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 3
ER -