Global identification of Small Ubiquitin-related Modifier (SUMO) substrates reveals crosstalk between SUMOylation and phosphorylation promotes cell migration

Ijeoma Uzoma, Jianfei Hu, Eric Cox, Shuli Xia, Jianying Zhou, Hee Sool Rho, Catherine Guzzo, Corry Paul, Olutobi Ajala, C. Rory Goodwin, Junseop Jeong, Cedric Moore, Hui Zhang, Pamela Meluh, Seth Blackshaw, Michael Matunis, Jiang Qian, Heng Zhu

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)871-888
Number of pages18
JournalMolecular and Cellular Proteomics
Volume17
Issue number5
DOIs
StatePublished - May 2018

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Molecular Biology

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