MAP Kinase: SUMO Pathway Interactions
The convergence and coordinated cross talk of different signalling pathways forms a regulatory network which determines the biological outcome to environmental cues. The MAPK pathways are one of the important routes by which extracellular signals are tran
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1. Introduction SUMO conjugation has emerged as an important post-translational modification and is part of an enzymatic cascade, involving an E1 activating enzyme (SAE1/2) and an E2-conjugating enzyme (Ubc9) Fig. 1a. A number of distinct classes of E3 ligases (including RanBP2, the PIAS family, and Pc2) have been identified that enhance the efficiency and specificity of sumoylation of target substrates in vivo (1, 2). Importantly, sumoylation is a reversible process. Several hydrolases [SUMO-specific proteases (SENPs)] that function to produce the mature SUMO paralogues, to remove the modifications Rony Seger (ed.), MAP Kinase Signaling Protocols: Second Edition, Methods in Molecular Biology, vol. 661, DOI 10.1007/978-1-60761-795-2_21, © Springer Science+Business Media, LLC 2010
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a SUMO
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Fig. 1. (a) The SUMO Cycle. The mature SUMO is activated by the SAE1/SAE2 enzyme (E1). The SUMO ~ Ubc9 is formed after transesterification of SUMO onto the SUMO conjugating enzyme, Ubc9, (E2). Subsequently, the target protein (X) is selected in an E3 ligase-dependent or independent manner, and the SUMO is ligated to the substrate through isopeptide-bound linkage (SUMO-X). SUMO modification can be reversed from target proteins by the action of SUMO-specific proteases and potentially be reused in the SUMO cycle. (b) A diagram depicting the example routes which encompass the interplay between the SUMO and MAPK pathways in the regulation of gene transcription. The sequential action of these pathways on Elk-1 (left panel) and PEA3 (right panel) are shown. Left panel: The SUMO and ERK pathways combine to regulate the transcriptional activity of Elk-1. The transcriptionally inert state of Elk-1 is controlled by its sumoylation via recruiting a HDAC2-containing corepressor complex. The ERK MAPK triggers a series of molecular events, which result in the loss of Elk-1 sumoylation, and hence, release of the co-repressor complex. At the same time, Elk-1 is phosphorylated (-P) and this converts Elk-1 into a transient, highly active state. Right panel: MAP kinase signaling initiates a cascade that initially promotes PEA3 sumoylation (PEA3-SUMO) and enhances its transactivation properties. This is important for polyubiquitination (Ub) and eventual turnover of PEA3. The polyubiquitination might potentially occurs on the SUMO moiety and/or PEA3 itself. The question mark represents the unknown transcriptional activity of these forms of PEA3.
completely or edit chains of SUMO moieties, have been identified (3). Sumoylation usually occurs on an acceptor lysine residue of a substrate at the core SUMO consensus motif, YKxE (4, 5). In addition to this core motif, a number of extended SUMO consensus motifs have been identified including the KEPE motif, SC motif, PDSM, and NDSM, which serve to further increase the specific
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