title: Ubiquitin-dependent regulation of MEKK2/3-MEK5-ERK5 signaling module by XIAP and cIAP1.
abstract: 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.
authors: Cell Death Signaling Group, Institute of Biochemistry II Goethe University Medical School, Frankfurt, Germany.
authors: Armelle-Natsuo
authors: AN
authors: Takeda
authors: Cell Death Signaling Group, Institute of Biochemistry II Goethe University Medical School, Frankfurt, Germany.
authors: Tripat Kaur
authors: TK
authors: Oberoi-Khanuja
authors: Department of Biochemistry, Eötvös Loránd University, Budapest, Hungary Institute of Enzymology, Research Centre for Natural Sciences Hungarian Academy of Sciences, Budapest, Hungary.
authors: Gabor
authors: G
authors: Glatz
authors: Cell Death Signaling Group, Institute of Biochemistry II Goethe University Medical School, Frankfurt, Germany.
authors: Katharina
authors: K
authors: Schulenburg
authors: Cell Death Signaling Group, Institute of Biochemistry II Goethe University Medical School, Frankfurt, Germany.
authors: Rolf-Peter
authors: RP
authors: Scholz
authors: Proteome Center Tuebingen, Interfaculty Institute for Cell Biology University of Tuebingen, Tuebingen, Germany.
authors: Alejandro
authors: A
authors: Carpy
authors: Proteome Center Tuebingen, Interfaculty Institute for Cell Biology University of Tuebingen, Tuebingen, Germany.
authors: Boris
authors: B
authors: Macek
authors: Department of Biochemistry, Eötvös Loránd University, Budapest, Hungary Institute of Enzymology, Research Centre for Natural Sciences Hungarian Academy of Sciences, Budapest, Hungary.
authors: Attila
authors: A
authors: Remenyi
authors: Cell Death Signaling Group, Institute of Biochemistry II Goethe University Medical School, Frankfurt, Germany Krishna@biochem2.de.
authors: Krishnaraj
authors: K
authors: Rajalingam
mesh_terms: D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D048671:MAP Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D048730:MAP Kinase Kinase Kinase 2; D048748:MAP Kinase Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D051034:Inhibitor of Apoptosis Proteins; D064326:MEF2 Transcription Factors; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D014157:Transcription Factors; D025801:Ubiquitin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D048054:Mitogen-Activated Protein Kinase 7; D048730:MAP Kinase Kinase Kinase 2; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; C482618:MAP3K2 protein, human; C482625:MAP3K3 protein, human; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human
keywords: ERK5; IAP; MAPK; myoblasts; ubiquitin