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Ubiquitin‐dependent regulation of MEKK 2/3‐ MEK 5‐ ERK 5 signaling module by XIAP and c IAP 1
Author(s) -
Takeda ArmelleNatsuo,
OberoiKhanuja Tripat Kaur,
Glatz Gabor,
Schulenburg Katharina,
Scholz RolfPeter,
Carpy Alejandro,
Macek Boris,
Remenyi Attila,
Rajalingam Krishnaraj
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201487808
Subject(s) - biology , mapk/erk pathway , mek inhibitor , microbiology and biotechnology , kinase
Mitogen‐activated protein kinases ( MAPK s) are highly conserved protein kinase modules, and they control fundamental cellular processes. While the activation of MAPK s 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 ( ERK 5) is a unique, conserved member of the MAPK family and is activated in response to various stimuli through a three‐tier cascade constituting MEK 5 and MEKK 2/3. We reveal an unexpected role for Inhibitors of Apoptosis Proteins ( IAP s) in the inactivation of ERK 5 pathway in a bimodal manner involving direct interaction and ubiquitination. XIAP directly interacts with MEKK 2/3 and competes with PB 1 domain‐mediated binding to MEK 5. XIAP and c IAP 1 conjugate predominantly K63‐linked ubiquitin chains to MEKK 2 and MEKK 3 which directly impede MEK 5– ERK 5 interaction in a trimeric complex leading to ERK 5 inactivation. Consistently, loss of XIAP or c IAP 1 by various strategies leads to hyperactivation of ERK 5 in normal and tumorigenic cells. Loss of XIAP promotes differentiation of human primary skeletal myoblasts to myocytes in a MEKK 2/3‐ ERK 5‐dependent manner. Our results reveal a novel, obligatory role for IAP s and ubiquitination in the physical and functional disassembly of ERK 5‐ MAPK module and human muscle cell differentiation.