Correction to: MYO1D binds with kinase domain of the EGFR family to anchor them to plasma membrane before their activation and contributes carcinogenesis

The retroviral oncogene v-erb-B encodes a truncated version of the receptor for epidermal growth factor. To define the disposition of the v-erb-B protein within cells and across the plasma membrane, we raised antibodies against defined epitopes in the protein and used these in immunofluorescence to analyze cells transformed by v-erb-B. A small fraction of the v-erb-B protein was found on the plasma membrane in a clustered configuration. The bulk of the protein was located in the endoplasmic reticulum and Golgi apparatus. Epitopes near the amino terminus of the v-erb-B protein were displayed on the surface of the cell, whereas epitopes in the protein kinase domain were located exclusively within cells. We conclude that the v-erb-B protein spans the plasma membrane in a manner similar or identical to that of the epidermal growth factor receptor, even though the viral transforming protein does not possess the signal peptide that is thought to direct insertion of the receptor into the membrane.

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Lipid-dependent Akt-ivity: where, when, and how

Biochemical Society Transactions ◽

10.1042/bst20190013 ◽

2019 ◽

Vol 47 (3) ◽

pp. 897-908 ◽

Cited By ~ 3

Author(s):

Katharina M. Siess ◽

Thomas A. Leonard

Keyword(s):

Plasma Membrane ◽

Protein Kinase ◽

Kinase Domain ◽

Target Of Rapamycin ◽

Endomembrane System ◽

Essential Protein ◽

Mechanistic Target Of Rapamycin ◽

Subcellular Compartments ◽

Membrane Bound ◽

Phosphoinositide 3 Kinase

Abstract Akt is an essential protein kinase activated downstream of phosphoinositide 3-kinase and frequently hyperactivated in cancer. Canonically, Akt is activated by phosphoinositide-dependent kinase 1 and mechanistic target of rapamycin complex 2, which phosphorylate it on two regulatory residues in its kinase domain upon targeting of Akt to the plasma membrane by PI(3,4,5)P3. Recent evidence, however, has shown that, in addition to phosphorylation, Akt activity is allosterically coupled to the engagement of PI(3,4,5)P3 or PI(3,4)P2 in cellular membranes. Furthermore, the active membrane-bound conformation of Akt is protected from dephosphorylation, and Akt inactivation by phosphatases is rate-limited by its dissociation. Thus, Akt activity is restricted to membranes containing either PI(3,4,5)P3 or PI(3,4)P2. While PI(3,4,5)P3 has long been associated with signaling at the plasma membrane, PI(3,4)P2 is gaining increasing traction as a signaling lipid and has been implicated in controlling Akt activity throughout the endomembrane system. This has clear implications for the phosphorylation of both freely diffusible substrates and those localized to discrete subcellular compartments.

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Partners in Crime: The Interplay of Proteins and Membranes in Regulated Necrosis

International Journal of Molecular Sciences ◽

10.3390/ijms21072412 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2412 ◽

Cited By ~ 4

Author(s):

Uris Ros ◽

Lohans Pedrera ◽

Ana J. Garcia-Saez

Keyword(s):

Cell Death ◽

Plasma Membrane ◽

Membrane Damage ◽

Kinase Domain ◽

Membrane Permeabilization ◽

Plasma Membrane Damage ◽

Intracellular Content ◽

Regulated Necrosis ◽

Inflammatory Phenotype ◽

Cellular Components

Pyroptosis, necroptosis, and ferroptosis are well-characterized forms of regulated necrosis that have been associated with human diseases. During regulated necrosis, plasma membrane damage facilitates the movement of ions and molecules across the bilayer, which finally leads to cell lysis and release of intracellular content. Therefore, these types of cell death have an inflammatory phenotype. Each type of regulated necrosis is mediated by a defined machinery comprising protein and lipid molecules. Here, we discuss how the interaction and reshaping of these cellular components are essential and distinctive processes during pyroptosis, necroptosis, and ferroptosis. We point out that although the plasma membrane is the common target in regulated necrosis, different mechanisms of permeabilization have emerged depending on the cell death form. Pore formation by gasdermins (GSDMs) is a hallmark of pyroptosis, while mixed lineage kinase domain-like (MLKL) protein facilitates membrane permeabilization in necroptosis, and phospholipid peroxidation leads to membrane damage in ferroptosis. This diverse repertoire of mechanisms leading to membrane permeabilization contributes to define the specific inflammatory and immunological outcome of each type of regulated necrosis. Current efforts are focused on new therapies that target critical protein and lipid molecules on these pathways to fight human pathologies associated with inflammation.

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Inhibition of ErbB3 by a monoclonal antibody that locks the extracellular domain in an inactive configuration

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1518361112 ◽

2015 ◽

Vol 112 (43) ◽

pp. 13225-13230 ◽

Cited By ~ 20

Author(s):

Sangwon Lee ◽

Etienne B. Greenlee ◽

Joseph R. Amick ◽

Gwenda F. Ligon ◽

Jay S. Lillquist ◽

...

Keyword(s):

Monoclonal Antibody ◽

Tyrosine Kinases ◽

Egf Receptor ◽

Human Cancer ◽

Extracellular Domain ◽

Kinase Domain ◽

Tyrosine Kinase Domain ◽

Fab Fragment ◽

Allosteric Mechanism ◽

Egfr Family

ErbB3 (HER3) is a member of the EGF receptor (EGFR) family of receptor tyrosine kinases, which, unlike the other three family members, contains a pseudo kinase in place of a tyrosine kinase domain. In cancer, ErbB3 activation is driven by a ligand-dependent mechanism through the formation of heterodimers with EGFR, ErbB2, or ErbB4 or via a ligand-independent process through heterodimerization with ErbB2 overexpressed in breast tumors or other cancers. Here we describe the crystal structure of the Fab fragment of an antagonistic monoclonal antibody KTN3379, currently in clinical development in human cancer patients, in complex with the ErbB3 extracellular domain. The structure reveals a unique allosteric mechanism for inhibition of ligand-dependent or ligand-independent ErbB3-driven cancers by binding to an epitope that locks ErbB3 in an inactive conformation. Given the similarities in the mechanism of ErbB receptor family activation, these findings could facilitate structure-based design of antibodies that inhibit EGFR and ErbB4 by an allosteric mechanism.

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Proximity of the EGF Receptor Kinase Domain To the Plasma Membrane

Biophysical Journal ◽

10.1016/j.bpj.2009.12.281 ◽

2010 ◽

Vol 98 (3) ◽

pp. 49a

Author(s):

Ping Liu ◽

Stuart McLaughlin

Keyword(s):

Plasma Membrane ◽

Egf Receptor ◽

Kinase Domain ◽

Receptor Kinase

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Identification and Gene Expression Analysis of a Large Family of Transmembrane Kinases Related to the Gal/GalNAc Lectin in Entamoeba histolytica

Eukaryotic Cell ◽

10.1128/ec.4.4.722-732.2005 ◽

2005 ◽

Vol 4 (4) ◽

pp. 722-732 ◽

Cited By ~ 55

Author(s):

David L. Beck ◽

Douglas R. Boettner ◽

Bojan Dragulev ◽

Kim Ready ◽

Tomoyoshi Nozaki ◽

...

Keyword(s):

Plasma Membrane ◽

Entamoeba Histolytica ◽

Tyrosine Kinases ◽

Large Family ◽

Kinase Domain ◽

Phylogenetic Groups ◽

Significant Similarity ◽

Dual Specificity ◽

Extracellular Stimuli ◽

Molecular Masses

ABSTRACT We identified in the Entamoeba histolytica genome a family of over 80 putative transmembrane kinases (TMKs). The TMK extracellular domains had significant similarity to the intermediate subunit (Igl) of the parasite Gal/GalNAc lectin. The closest homolog to the E. histolytica TMK kinase domain was a cytoplasmic dual-specificity kinase, SplA, from Dictyostelium discoideum. Sequence analysis of the TMK family demonstrated similarities to both serine/threonine and tyrosine kinases. TMK genes from each of six phylogenetic groups were expressed as mRNA in trophozoites, as assessed by spotted oligoarray and real-time PCR assays, suggesting nonredundant functions of the TMK groups for sensing and responding to extracellular stimuli. Additionally, we observed changes in the expression profile of the TMKs in continuous culture. Antisera produced against the conserved kinase domain identified proteins of the expected molecular masses of the expressed TMKs. Confocal microscopy with anti-TMK kinase antibodies revealed a focal distribution of the TMKs on the cytoplasmic face of the trophozoite plasma membrane. We conclude that E. histolytica expresses members of each subgroup of TMKs. The presence of multiple receptor kinases in the plasma membrane offers for the first time a potential explanation of the ability of the parasite to respond to the changing environment of the host.

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Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death

Cell Research ◽

10.1038/cr.2013.171 ◽

2013 ◽

Vol 24 (1) ◽

pp. 105-121 ◽

Cited By ~ 384

Author(s):

Xin Chen ◽

Wenjuan Li ◽

Junming Ren ◽

Deli Huang ◽

Wan-ting He ◽

...

Keyword(s):

Cell Death ◽

Plasma Membrane ◽

Kinase Domain ◽

Necrotic Cell Death ◽

Necrotic Cell ◽

Mixed Lineage Kinase

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Oligomerization-driven MLKL ubiquitylation antagonises necroptosis

10.1101/2021.05.01.442209 ◽

2021 ◽

Author(s):

Zikou Liu ◽

Laura Francesca Dagley ◽

Kristy Lynn Shield-Artin ◽

Samuel Nicholas Young ◽

Aleksandra Bankovacki ◽

...

Keyword(s):

Cell Death ◽

Plasma Membrane ◽

Protein Kinase ◽

Kinase Domain ◽

Membrane Disruption ◽

Fusion Strategy ◽

Mixed Lineage Kinase ◽

Independent Form ◽

Lysine Residues ◽

Kinetic Regulation

Mixed lineage kinase domain-like (MLKL) is the executioner in the caspase-independent form of programmed cell death called necroptosis. Receptor Interacting serine/threonine Protein Kinase 3 (RIPK3) phosphorylates MLKL, triggering MLKL oligomerization, membrane translocation and membrane disruption. MLKL also undergoes ubiquitylation during necroptosis, yet neither the mechanism nor significance of this event have been demonstrated. Here we show that necroptosis-specific, multi-mono-ubiquitylation of MLKL occurs following its activation and oligomerization. Ubiquitylated MLKL accumulates in a digitonin insoluble cell fraction comprising plasma/organellar membranes and protein aggregates. This ubiquitylated form is diminished by a plasma membrane located deubiquitylating enzyme. MLKL is ubiquitylated on at least 4 separate lysine residues once oligomerized, and this correlates with proteasome- and lysosome- dependent turnover. Using a MLKL-DUB fusion strategy, we show that constitutive removal of ubiquitin from MLKL licenses MLKL auto-activity independent of necroptosis signalling in mouse and human cells. Therefore, besides its role in the kinetic regulation of MLKL-induced death following an exogenous necroptotic stimulus, ubiquitylation also contributes to the restraint of basal levels of activated MLKL to avoid errant cell death.

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The MLKL Channel in Necroptosis Is an Octamer Formed by Tetramers in a Dyadic Process

Molecular and Cellular Biology ◽

10.1128/mcb.00497-16 ◽

2016 ◽

Vol 37 (5) ◽

Cited By ~ 42

Author(s):

Deli Huang ◽

Xinru Zheng ◽

Zi-an Wang ◽

Xin Chen ◽

Wan-ting He ◽

...

Keyword(s):

Plasma Membrane ◽

Disulfide Bond ◽

Disulfide Bonds ◽

Kinase Domain ◽

Cation Channel ◽

Membrane Translocation ◽

Mixed Lineage Kinase ◽

Channel Function ◽

Symmetry Model ◽

Dyadic Process

ABSTRACT Oligomerization of the mixed-lineage kinase domain-like protein (MLKL) is essential for its cation channel function in necroptosis. Here we show that the MLKL channel is an octamer comprising two previously identified tetramers most likely in their side-by-side position. Intermolecule disulfide bonds are present in the tetramer but are not required for octamer assembly and necroptosis. MLKL forms oligomers in the necrosome and is then released from the necrosome before or during its membrane translocation. We identified two MLKL mutants that could not oligomerize into octamers, although they formed a tetramer, and also, one MLKL mutant could spontaneously form a disulfide bond-linked octamer. Subsequent analysis revealed that the tetramers fail to translocate to the plasma membrane and that the MLKL octamer formation depends on α-helices 4 and 5. While MLKL could be detected from outside the cells, its N- and C-terminal ends could not be detected, indicating that the MLKL octamer spans across the plasma membrane, leaving its N and C termini inside the cell. These data allowed us to propose a 180° symmetry model of the MLKL octamer and conclude that the fully assembled MLKL octamers, but not the previously described tetramers, act as effectors of necroptosis.

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