Src activates retrograde membrane traffic through phosphorylation of GBF1

The Src tyrosine kinase controls cancer-critical protein glycosylation through Golgi to ER relocation of GALNTs enzymes. How Src induces this trafficking event is unknown. Golgi to ER transport depends on the GTP exchange factor (GEF) GBF1 and small GTPase Arf1. Here, we show that Src induces the fo...

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Bibliographic Details
Published in:eLife 2021-12, Vol.10
Main Authors: Chia, Joanne, Wang, Shyi-Chyi, Wee, Sheena, Gill, David James, Tay, Felicia, Kannan, Srinivasaraghavan, Verma, Chandra S, Gunaratne, Jayantha, Bard, Frederic A
Format: Article
Language:English
Subjects:
Analysis
Arf1
Automation
C-Terminus
Cell Biology
Endoplasmic reticulum
Endoplasmic Reticulum - metabolism
Enzymes
GBF1
Glycosylation
golgi
Golgi apparatus
Golgi Apparatus - metabolism
Guanine Nucleotide Exchange Factors - genetics
Guanine Nucleotide Exchange Factors - metabolism
Humans
Lectins
Localization
membrane traffic
Membrane trafficking
Membranes
Molecular modelling
Mutants
Phosphorylation
Protein Transport
Protein-tyrosine kinase
Proteins
signalling
Src
Src protein
src-Family Kinases - genetics
src-Family Kinases - metabolism
Tubules
Tumors
Tyrosine
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Summary:The Src tyrosine kinase controls cancer-critical protein glycosylation through Golgi to ER relocation of GALNTs enzymes. How Src induces this trafficking event is unknown. Golgi to ER transport depends on the GTP exchange factor (GEF) GBF1 and small GTPase Arf1. Here, we show that Src induces the formation of tubular transport carriers containing GALNTs. The kinase phosphorylates GBF1 on 10 tyrosine residues; two of them, Y876 and Y898, are located near the C-terminus of the Sec7 GEF domain. Their phosphorylation promotes GBF1 binding to the GTPase; molecular modeling suggests partial melting of the Sec7 domain and intramolecular rearrangement. GBF1 mutants defective for these rearrangements prevent binding, carrier formation, and GALNTs relocation, while phosphomimetic GBF1 mutants induce tubules. In sum, Src promotes GALNTs relocation by promoting GBF1 binding to Arf1. Based on residue conservation, similar regulation of GEF-Arf complexes by tyrosine phosphorylation could be a conserved and widespread mechanism.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.68678