Monoubiquitinylation regulates endosomal localization of Lst2, a negative regulator of EGF receptor signaling.
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.
Mosesson
Yaron
Y
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Chetrit
David
D
Schley
Leehee
L
Berghoff
Janina
J
Ziv
Tamar
T
Carvalho
Silvia
S
Milanezi
Fernanda
F
Admon
Arie
A
Schmitt
Fernando
F
Ehrlich
Marcelo
M
Yarden
Yosef
Y
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000378:metabolism; D004705:Endocytosis; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000737:chemistry; D066246:ErbB Receptors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008565:Membrane Proteins; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D054875:Ubiquitination; D016335:Zinc Fingers
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; D010750:Phosphoproteins; C426543:TRIM3 protein, human; C541183:ZFYVE28 protein, human; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D066246:ErbB Receptors; D008239:Lysine