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Mol Cell Proteomics. 2018 May;17(5):871-888. doi: 10.1074/mcp.RA117.000014. Epub 2018 Feb 8.

Global Identification of Small Ubiquitin-related Modifier (SUMO) Substrates Reveals Crosstalk between SUMOylation and Phosphorylation Promotes Cell Migration.

Author information

1
From the ‡Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
2
§The Center for High-Throughput Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
3
¶Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
4
‖Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
5
**Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
6
‡‡Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland 21205.
7
§§Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
8
¶¶Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205.
9
From the ‡Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; hzhu4@jhmi.edu.

Abstract

Proteomics studies have revealed that SUMOylation is a widely used post-translational modification (PTM) in eukaryotes. However, how SUMO E1/2/3 complexes use different SUMO isoforms and recognize substrates remains largely unknown. Using a human proteome microarray-based activity screen, we identified over 2500 proteins that undergo SUMO E3-dependent SUMOylation. We next constructed a SUMO isoform- and E3 ligase-dependent enzyme-substrate relationship network. Protein kinases were significantly enriched among SUMOylation substrates, suggesting crosstalk between phosphorylation and SUMOylation. Cell-based analyses of tyrosine kinase, PYK2, revealed that SUMOylation at four lysine residues promoted PYK2 autophosphorylation at tyrosine 402, which in turn enhanced its interaction with SRC and full activation of the SRC-PYK2 complex. SUMOylation on WT but not the 4KR mutant of PYK2 further elevated phosphorylation of the downstream components in the focal adhesion pathway, such as paxillin and Erk1/2, leading to significantly enhanced cell migration during wound healing. These studies illustrate how our SUMO E3 ligase-substrate network can be used to explore crosstalk between SUMOylation and other PTMs in many biological processes.

PMID:
29438996
PMCID:
PMC5930406
DOI:
10.1074/mcp.RA117.000014
[Indexed for MEDLINE]
Free PMC Article

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