Ubiquitin Chains in the Ladder of MAPK Signaling

Abstract

With a better understanding of the cellular stress response, it has become evident that catalytic modules consisting of kinases that mediate the activation of downstream effector components are subject to multiple layers of regulation. Such regulatory mechanisms are not limited to those involving scaffold proteins or protein phosphatases, and they appear to include a growing number of modifications by ubiquitin and ubiquitin-like proteins. The role of ubiquitin in the regulation of mitogen-activated protein kinase (MAPK) emerges as a paradigm for understanding the role of ubiquitination in regulating other signal transduction pathways. Ubiquitination influences signal diversification and limits the duration of the signal through its role in the assembly of protein kinase complexes, subcellular localization, and the actual degradation of the kinase or its substrate. This review summarizes our current understanding of the roles of ubiquitin in regulating MAPK signaling.

Phosphorylation-Dependent Lys63-Linked Polyubiquitination of Daxx Is Essential for Sustained TNF-α–Induced ASK1 Activation

“…One such example is Lys 63 (K63)-mediated polyubiquitination, which can mediate cellular signaling, DNA repair, protein localization, and endocytosis (8)(9)(10). The ubiquitin ligases TNF-associated factors 2 and 6, which harbor intact RING finger domains, mediate K63-linked polyubiquitination of themselves as well as stress-responsive kinases in signaling pathways activating JNK, p38, and IKK (11). Therefore, it is likely that the mode of ubiquitin chain linkage is closely related to their biological functions.…”

The PP2C Alphabet Is a Negative Regulator of Stress-Activated Protein Kinase Signaling in Drosophila

“…Given the variety of extracellular signals and MAPKKKs involved in SAPK activation, cells must possess mechanisms to elicit specific cellular responses. These mechanisms are currently being unraveled and appear to depend on specific scaffolds (Dhanasekaran et al 2007), phosphatases (Owens and Keyse 2007), and components of the ubiquitin/ proteasome complex (Laine and Ronai 2005) that shape signaling paths and modulate internal signaling flow. Nonetheless, the way in which these proteins work together to produce specific outputs remains largely unexplored.…”

Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses

“…Unlike K48-linked ubiquitin polymers, these K63-linked ubiquitin chains are not substrates for the proteasome (5,6). Instead, K63-linked polyubiquitination plays roles in protein activation, protein interactions, and subcellular targeting of proteins (7)(8)(9).…”