scholarly journals Adhesion-induced eosinophil cytolysis requires the receptor-interacting protein kinase 3 (RIPK3)–mixed lineage kinase-like (MLKL) signaling pathway, which is counterregulated by autophagy

2017 ◽  
Vol 140 (6) ◽  
pp. 1632-1642 ◽  
Author(s):  
Susanne Radonjic-Hoesli ◽  
Xiaoliang Wang ◽  
Elisabeth de Graauw ◽  
Christina Stoeckle ◽  
Beata Styp-Rekowska ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Interacting Protein ◽  
Mixed Lineage Kinase

scholarly journals Protein kinase G I alpha activates an anti-remodeling signaling pathway in the heart via an interaction with the MAPKKK mixed lineage kinase 3

2011 ◽  
Vol 11 (S1) ◽  
Author(s):  
Robert M Blanton ◽  
Eiki Takimoto ◽  
Angela Lane ◽  
Mark J Aronovitz ◽  
Richard H Karas ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Protein Kinase G ◽  
Mixed Lineage Kinase ◽  
Mixed Lineage Kinase 3

scholarly journals Diverse Sequence Determinants Control Human and Mouse Receptor Interacting Protein 3 (RIP3) and Mixed Lineage Kinase domain-Like (MLKL) Interaction in Necroptotic Signaling

2013 ◽  
Vol 288 (23) ◽  
pp. 16247-16261 ◽  
Author(s):  
Wanze Chen ◽  
Zhenru Zhou ◽  
Lisheng Li ◽  
Chuan-Qi Zhong ◽  
Xinru Zheng ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Kinase Domain ◽  
Phosphorylation Sites ◽  
Flanking Sequence ◽  
Interacting Protein ◽  
Mixed Lineage Kinase ◽  
Signaling Complex ◽  
Evolutionarily Conserved ◽  
Mouse Cells ◽  
Human And Mouse

Receptor interacting protein 3 (RIP3) is a protein kinase essential for TNF-induced necroptosis. Phosphorylation on Ser-227 in human RIP3 (hRIP3) is required for its interaction with human mixed lineage kinase domain-like (MLKL) in the necrosome, a signaling complex induced by TNF stimulation. RIP1 and RIP3 mediate necrosome aggregation leading to the formation of amyloid-like signaling complexes. We found that TNF induces Thr-231 and Ser-232 phosphorylation in mouse RIP3 (mRIP3) and this phosphorylation is required for mRIP3 to interact with mMLKL. Ser-232 in mRIP3 corresponds to Ser-227 in hRIP3, whereas Thr-231 is not conserved in hRIP3. Although the RIP3-MLKL interaction is required for necroptosis in both human and mouse cells, hRIP3 does not interact with mMLKL and mRIP3 cannot bind to hMLKL. The species specificity of the RIP3-MLKL interaction is primarily determined by the sequence differences in the phosphorylation sites and the flanking sequence around the phosphorylation sites in hRIP3 and mRIP3. It appears that the RIP3-MLKL interaction has been selected as an evolutionarily conserved mechanism in mediating necroptosis signaling despite that differing structural and mechanistic bases for this interaction emerged simultaneously in different organisms. In addition, we further revealed that the interaction of RIP3 with MLKL prevented massive abnormal RIP3 aggregation, and therefore should be crucial for formation of the amyloid signaling complex of necrosomes. We also found that the interaction between RIP3 and MLKL is required for the translocation of necrosomes to mitochondria-associated membranes. Our data demonstrate the importance of the RIP3-MLKL interaction in the formation of functional necrosomes and suggest that translocation of necrosomes to mitochondria-associated membranes is essential for necroptosis signaling.

scholarly journals Cyclic AMP Stimulates SF-1-Dependent CYP11A1 Expression through Homeodomain-Interacting Protein Kinase 3-Mediated Jun N-Terminal Kinase and c-Jun Phosphorylation

2007 ◽  
Vol 27 (6) ◽  
pp. 2027-2036 ◽  
Author(s):  
Hsin-Chieh Lan ◽  
Hua-Jung Li ◽  
Guang Lin ◽  
Pao-Yen Lai ◽  
Bon-chu Chung
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Cyclic Amp ◽  
Signaling Pathway ◽  
Camp Signaling ◽  
Functional Interaction ◽  
Interacting Protein ◽  
Surface Receptors ◽  
Camp Signaling Pathway ◽  
Camp Stimulation

ABSTRACT Steroids are synthesized in adrenal glands and gonads under the control of pituitary peptides. These peptides bind to cell surface receptors to activate the cyclic AMP (cAMP) signaling pathway leading to an increase of steroidogenic gene expression. Exactly how cAMP activates steroidogenic gene expression is not clear, except for the knowledge that transcription factor SF-1 plays a key role. Investigating the factors participating in SF-1 action, we found that c-Jun and homeodomain-interacting protein kinase 3 (HIPK3) were required for basal and cAMP-stimulated expression of one major steroidogenic gene, CYP11A1. HIPK3 enhanced SF-1 activity, and c-Jun was required for the functional interaction of HIPK3 with SF-1. Furthermore, after cAMP stimulation, both c-Jun and Jun N-terminal kinase (JNK) were phosphorylated through HIPK3. These phosphorylations were important for SF-1 activity and CYP11A1 expression. Thus, we have defined HIPK3-mediated JNK activity and c-Jun phosphorylation as important events that increase SF-1 activity for CYP11A1 transcription in response to cAMP. This finding has linked three common factors, HIPK3, JNK, and c-Jun, to the cAMP signaling pathway leading to increased steroidogenic gene expression.

scholarly journals Uncovering human mixed lineage kinase domain-like activation in necroptosis

2019 ◽  
Vol 11 (21) ◽  
pp. 2831-2844
Author(s):  
Cristina D Guibao ◽  
Katherine Petrinjak ◽  
Tudor Moldoveanu
Keyword(s):  
Plasma Membrane ◽  
Protein Kinase ◽  
Recent Progress ◽  
Inositol Phosphate ◽  
Kinase Domain ◽  
Structural Studies ◽  
Interacting Protein ◽  
Mixed Lineage Kinase ◽  
Membrane Rupture ◽  
Essential Components

MLKL and its obligate upstream receptor interacting protein kinase 3 are essential components of necroptosis. It is well established that MLKL is the executioner of plasma membrane rupture in necroptosis. In healthy cells MLKL is dormant. Several dormant configurations have emerged from high-resolution structural studies revealing distinct mechanisms of MLKL autoinhibition in mammals. MLKL is activated through the concerted actions of receptor interacting protein kinase 3, which phosphorylates MLKL, and, in the case of the human pathway, inositol phosphate (IP) metabolites synthesized by the IP kinases of the IP metabolic pathway. Here, we highlight recent progress toward understanding the mechanisms of regulation of human MLKL, and survey the latest opportunities for targeting MLKL in pathophysiology.

Expression of Receptor Interacting Protein Kinase-3 and Mixed Lineage Kinase Domain-Like Protein in Patients with COPD

2019 ◽  
Author(s):  
F. Verhamme ◽  
H.P. Van Eeckhoutte ◽  
T. Buyle-Huybrecht ◽  
G.G. Brusselle ◽  
P. Vandenabeele ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Kinase Domain ◽  
Interacting Protein ◽  
Mixed Lineage Kinase

scholarly journals Pannexin-1 Channels govern the Generation of Necroptotic small Extracellular Vesicles

2019 ◽  
Author(s):  
Tiphaine Douanne ◽  
Gwennan André-Grégoire ◽  
Magalie Feyeux ◽  
Philippe Hulin ◽  
Julie Gavard ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Protein Kinase ◽  
Extracellular Vesicles ◽  
Molecular Basis ◽  
Membrane Integrity ◽  
Rab Gtpase ◽  
Interacting Protein ◽  
Plasma Membrane Integrity ◽  
Mixed Lineage Kinase ◽  
Pannexin 1

ABSTRACTThe activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) controls the execution of necroptosis, a regulated form of necrosis that occurs in apoptosis-deficient conditions. Active oligomerized MLKL triggers the exposure of phosphatidylserine residues on the cell surface and disrupts the plasma membrane integrity by forming lytic pores. MLKL also governs the biogenesis and shedding of proinflammatory small extracellular vesicles (EVs) during the early steps of necroptosis, however the molecular basis is unknown. Here, we find that MLKL oligomers activate plasma membrane Pannexin-1 (PANX1) channels, concomitantly to the loss of phosphatidylserine asymmetry. This plasma membrane “leakiness” requires the Rab GTPase Rab27 isoforms, which usher the small EVs to their release. Conversely, PANX1 knockdown disorganized the small EVs machinery and precludes vesicles extrusion. These data identify a novel signaling nexus between MLKL, Rab27, and PANX1, and propose ways to interfere with small EV generation.

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