Global Map of SUMO Function Revealed by Protein-Protein Interaction and Genetic Networks

Makhnevych, Taras; Sydorskyy, Yaroslav; X, Xin; Srikumar, Tharan; Vizeacoumar, Franco J.; Jeram, Stanley M.; Z, Li; Bahr, Sondra; Andrews, Brenda; Boone, Charles; Raught, Brian

doi:10.1016/j.molcel.2008.12.025

Cited by 114 publications

(109 citation statements)

References 59 publications

(86 reference statements)

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“…In this study, we discovered that SUMOylated proteins were specifically enriched in the ginkgolic acidregulated phosphoprotein group, making a direct link between SUMOylation and phosphorylation. Gene ontology analysis of the up-and down-regulated group showed that these phosphoproteins are mainly involved in transcriptional regulation, cell cycle regulation, and DNA replication, which are consistent with the known roles of SUMO in these cellular processes (3,5,23,24).…”

Section: Discussionsupporting

confidence: 76%

SUMOylation-regulated Protein Phosphorylation, Evidence from Quantitative Phosphoproteomics Analyses

Yao

Liu

et al. 2011

Journal of Biological Chemistry

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Protein modification is critical for the regulation of protein functions. Cross-talks among different types of protein modifications should yield concerted and coordinated regulatory networks for physiological functions. Here we have employed system-wide and quantitative phosphoproteomics analyses to reveal a global cross-talk for SUMOylation-modulated phosphorylation. Furthermore, as specific examples, we have shown that the ␣ subunit of casein kinase II is SUMOylated and that this affects the phosphorylation of its substrates. SUMO-regulated phosphorylation is involved in cell cycle control. Our data demonstrate an interplay between protein SUMOylation and phosphorylation and imply a regulatory role for this SUMOylation-modulated phosphorylation.The small ubiquitin-like modifiers (SUMOs) 3 belong to a subfamily of an ubiquitin-like protein superfamily. The covalent protein modification by SUMO affects a broad range of cellular activities. There are four human SUMO genes: SUMO1, SUMO2, SUMO3, and SUMO4. SUMO2 and SUMO3 share 97% amino acid sequence identity, whereasϳ50% identity is shared by SUMO2/3 and SUMO1 (1). The SUMO2/3 proteins have the ability to form poly-SUMO chains through their internal K11 linkage, but SUMO1 does not. SUMO1 can only be conjugated to poly-SUMO2/3 chains for the termination of poly-SUMO chains (2). SUMO4 shows a similarity to SUMO2/3, but it is unclear whether it is a pseudogene.Although many advances in understanding the biochemistry of SUMOylation have been made during the past decades, progresses in large-scale identification of SUMO substrates were only made in recent years. In contrast to the traditional approach for the identification of SUMOylated proteins, which was mostly based on immunoblotting of a known protein (a hypothesis-driven process), an affinity enrichment/purification strategy coupled with mass spectrometry-based protein analysis techniques (an unbiased screening process) is currently the most widely used approach (3-5). So far, ϳ800 putative SUMO substrates have been identified (3-9). These large-scale analyses have revealed important functions of the SUMO system in many biological processes, including RNA transcription, cell cycle, mRNA processing and splicing, as well as DNA metabolism and repair. However, the exact molecular mechanism by which the SUMO system plays its role in these cellular processes is poorly understood. There is much evidence from studies of individual proteins suggesting that SUMOylation and phosphorylation processes may be connected and cross-controlled (10 -13), but whether this is a general regulatory mechanism remains to be studied.Phosphorylation is the most extensively studied reversible posttranslational protein modification. Over 77,880 non-redundant phosphorylation sites on ϳ12,000 non-redundant proteins have been identified so far, according to PhosphoSitePlus, a database compiled by Cell Signaling Technology, Inc. More than 80% of the phosphorylation sites were identified by high throughput methods, primarily the mass spectrome...

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Section: Discussionsupporting

confidence: 76%

SUMOylation-regulated Protein Phosphorylation, Evidence from Quantitative Phosphoproteomics Analyses

Yao

Liu

et al. 2011

Journal of Biological Chemistry

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“…Among various potential targets, p53, an essential regulator of apoptosis and cell proliferation, appears to be a candidate because sumoylation of p53 has been reported to modulate its transcription activity (Gostissa et al, 1999;Rodriguez et al, 1999;Schmidt and Müller, 2002;Wu and Chiang, 2009). Another subclass of molecules potentially affected by the Sae1 Q273X mutation is those involved in DNA replication, including origin recognition complex 3, topoisomerase 1 and DNA replication helicase 2, as their activity is also modulated by sumoylation (Makhnevych et al, 2009). Further investigation will be required to identify the underlying molecular mechanism.…”

Section: Discussionmentioning

confidence: 99%

SUMO1-activating enzyme subunit 1 is essential for the survival of hematopoietic stem/progenitor cells in zebrafish

Lan

et al. 2012

Development

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In vertebrates, establishment of the hematopoietic stem/progenitor cell (HSPC) pool involves mobilization of these cells in successive developmental hematopoietic niches. In zebrafish, HSPCs originate from the ventral wall of the dorsal aorta (VDA), the equivalent of the mammalian aorta-gonad-mesonephros (AGM). The HSPCs subsequently migrate to the caudal hematopoietic tissue (CHT) for transitory expansion and differentiation during the larval stage, and they finally colonize the kidney, where hematopoiesis takes place in adult fish. Here, we report the isolation and characterization of a zebrafish mutant, tangohkz5, which shows defects of definitive hematopoiesis. In tangohkz5 mutants, HSPCs initiate normally in the AGM and subsequently colonize the CHT. However, definitive hematopoiesis is not sustained in the CHT owing to accelerated apoptosis and diminished proliferation of HSPCs. Positional cloning reveals that tangohkz5 encodes SUMO1-activating enzyme subunit 1 (Sae1). A chimera generation experiment and biochemistry analysis reveal that sae1 is cell-autonomously required for definitive hematopoiesis and that the tangohkz5 mutation produces a truncated Sae1 protein (ΔSae1), resulting in systemic reduction of sumoylation. Our findings demonstrate that sae1 is essential for the maintenance of HSPCs during fetal hematopoiesis in zebrafish.

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“…Global mapping of the SUMO network by protein-protein interactions and genetic-network analysis has linked SUMOylation to many different biological processes, including chromosome segregation and the cell cycle (Makhnevych et al, 2009). In recent years, the SUMO pathway has been implicated in several aspects of mitosis, including chromosome structure, cell-cycle progression, kinetochore function and cytokinesis (Dasso, 2008;Watts, 2007).…”

Section: Discussionmentioning

confidence: 99%

SUMOylation modulates the function of Aurora-B kinase

Fernández-Miranda

Castro

Carmena

et al. 2010

Journal of Cell Science

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SummaryAurora kinases are central regulators of mitotic-spindle assembly, chromosome segregation and cytokinesis. Aurora B is a member of the chromosomal passenger complex (CPC) with crucial functions in regulation of the attachment of kinetochores to microtubules and in cytokinesis. We report here that Aurora B contains a conserved SUMO modification motif within its kinase domain. Aurora B can bind SUMO peptides in vitro when bound to the IN-box domain of its CPC partner INCENP. Mutation of Lys207 to arginine (Aurora B K207R ) impairs the formation of conjugates of Aurora B and SUMO in vivo. Expression of the SUMO-null form of Aurora B results in abnormal chromosome segregation and cytokinesis failure and it is not able to rescue mitotic defects in Aurora-B-knockout cells. These defects are accompanied by increased levels of the CPC on chromosome arms and defective centromeric function, as detected by decreased phosphorylation of the Aurora-B substrate CENP-A. The Aurora-B K207R mutant does not display reduced kinase activity, suggesting that functional defects are probably a consequence of the altered localization, rather than decreased intrinsic kinase activity. These data suggest that SUMOylation of Aurora B modulates its function, possibly by mediating the extraction of CPC complexes from chromosome arms during prometaphase.

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Global Map of SUMO Function Revealed by Protein-Protein Interaction and Genetic Networks

Cited by 114 publications

References 59 publications

SUMOylation-regulated Protein Phosphorylation, Evidence from Quantitative Phosphoproteomics Analyses

SUMOylation-regulated Protein Phosphorylation, Evidence from Quantitative Phosphoproteomics Analyses

SUMO1-activating enzyme subunit 1 is essential for the survival of hematopoietic stem/progenitor cells in zebrafish

SUMOylation modulates the function of Aurora-B kinase

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