Mitogen-activated protein kinases (MAPKs) are highly conserved protein kinase modules, and they control fundamental cellular processes. While the activation of MAPKs has been well studied, little is known on the mechanisms driving their inactivation. Here we uncover a role for ubiquitination in the inactivation of a MAPK module. Extracellular-signal-regulated kinase 5 (ERK5) is a unique, conserved member of the MAPK family and is activated in response to various stimuli through a three-tier cascade constituting MEK5 and MEKK2/3. We reveal an unexpected role for Inhibitors of Apoptosis Proteins (IAPs) in the inactivation of ERK5 pathway in a bimodal manner involving direct interaction and ubiquitination. XIAP directly interacts with MEKK2/3 and competes with PB1 domain-mediated binding to MEK5. XIAP and cIAP1 conjugate predominantly K63-linked ubiquitin chains to MEKK2 and MEKK3 which directly impede MEK5-ERK5 interaction in a trimeric complex leading to ERK5 inactivation. Consistently, loss of XIAP or cIAP1 by various strategies leads to hyperactivation of ERK5 in normal and tumorigenic cells. Loss of XIAP promotes differentiation of human primary skeletal myoblasts to myocytes in a MEKK2/3-ERK5-dependent manner. Our results reveal a novel, obligatory role for IAPs and ubiquitination in the physical and functional disassembly of ERK5-MAPK module and human muscle cell differentiation. Synopsis Inhibitors of Apoptosis Proteins (IAPs) regulate myogenic differentiation by directly suppressing MEKK2/3-MEK5-ERK5 signaling, conceptually expanding the range of IAPs biological functions. Evidence for ubiquitination in physical and functional disassembly of a MAPK module. Reporting novel IAPs function in control of the MEKK2/3-MEK5-ERK5 cascade. This novel IAPs/MAPK interplay is functionally revealed in myogenic differentiation. Inhibitors of Apoptosis Proteins (IAPs) regulate myogenic differentiation by directly suppressing MEKK2/3-MEK5-ERK5 signaling, conceptually expanding the range of IAPs biological functions.
ASJC Scopus subject areas
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)