TY - JOUR
T1 - Monoubiquitinylation Regulates Endosomal Localization of Lst2, a Negative Regulator of EGF Receptor Signaling
AU - Mosesson, Yaron
AU - Chetrit, David
AU - Schley, Leehee
AU - Berghoff, Janina
AU - Ziv, Tamar
AU - Carvalho, Silvia
AU - Milanezi, Fernanda
AU - Admon, Arie
AU - Schmitt, Fernando
AU - Ehrlich, Marcelo
AU - Yarden, Yosef
N1 - Funding Information:
We thank S. Lev and S. Vincent (University of British Columbia) for plasmids. This work was supported in part by grants from the National Cancer Institute (grant CA72981), the German-Israel Foundation, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Israel Science Foundation funded by the Israel Academy of Sciences. Y.Y. is the Harold and Zelda Goldenberg Professorial Chair of Molecular Cell Biology.
PY - 2009/5/19
Y1 - 2009/5/19
N2 - Genetic screens performed in worms identified major regulators of the epidermal growth factor receptor (EGFR) pathway, including the ubiquitin ligase Cbl/SLI-1. Here we focus on the less-characterized Lst2 protein and confirm suppression of MAPK signals. Unexpectedly, human Lst2, a monoubiquitinylated phosphoprotein, does not localize to endosomes, despite an intrinsic phosphoinositol-binding FYVE domain. By constructing an ubiquitinylation-defective mutant and an ubiquitin fusion, we conclude that endosomal localization of Lst2, along with an ability to divert incoming EGFR molecules to degradation in lysosomes, is regulated by ubiquitinylation/deubiquitinylation cycles. Consistent with bifurcating roles, Lst2 physically binds Trim3/BERP, which interacts with Hrs and a complex that biases cargo recycling. These results establish an ubiquitin-based endosomal switch of receptor sorting, functionally equivalent to the mechanism inactivating Hrs via monoubiquitinylation.
AB - Genetic screens performed in worms identified major regulators of the epidermal growth factor receptor (EGFR) pathway, including the ubiquitin ligase Cbl/SLI-1. Here we focus on the less-characterized Lst2 protein and confirm suppression of MAPK signals. Unexpectedly, human Lst2, a monoubiquitinylated phosphoprotein, does not localize to endosomes, despite an intrinsic phosphoinositol-binding FYVE domain. By constructing an ubiquitinylation-defective mutant and an ubiquitin fusion, we conclude that endosomal localization of Lst2, along with an ability to divert incoming EGFR molecules to degradation in lysosomes, is regulated by ubiquitinylation/deubiquitinylation cycles. Consistent with bifurcating roles, Lst2 physically binds Trim3/BERP, which interacts with Hrs and a complex that biases cargo recycling. These results establish an ubiquitin-based endosomal switch of receptor sorting, functionally equivalent to the mechanism inactivating Hrs via monoubiquitinylation.
KW - CELLBIO
KW - SIGNALING
UR - http://www.scopus.com/inward/record.url?scp=65549163770&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2009.03.015
DO - 10.1016/j.devcel.2009.03.015
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AN - SCOPUS:65549163770
SN - 1534-5807
VL - 16
SP - 687
EP - 698
JO - Developmental Cell
JF - Developmental Cell
IS - 5
ER -