scholarly journals The dyslexia-associated protein KIAA0319 interacts with adaptor protein 2 and follows the classical clathrin-mediated endocytosis pathway

2009 ◽  
Vol 297 (1) ◽  
pp. C160-C168 ◽  
Author(s):  
Clotilde Levecque ◽  
Antonio Velayos-Baeza ◽  
Zoe G. Holloway ◽  
Anthony P. Monaco
Keyword(s):  
Neuronal Migration ◽  
Mammalian Cells ◽  
Adaptor Protein ◽  
Surface Expression ◽  
Learning Disorders ◽  
Endocytic Pathway ◽  
Fine Tuning ◽  
Genetic Studies ◽  
Binding Partner ◽  
Endocytosis Pathway

Recently, genetic studies have implicated KIAA0319 in developmental dyslexia, the most common of the childhood learning disorders. The first functional data indicated that the KIAA0319 protein is expressed on the plasma membrane and may be involved in neuronal migration. Further analysis of the subcellular distribution of the overexpressed protein in mammalian cells indicates that KIAA0319 can colocalize with the early endosomal marker early endosome antigen 1 (EEA1) in large intracellular vesicles, suggesting that it is endocytosed. Antibody internalization assays with full-length KIAA0319 and deletion constructs confirmed that KIAA0319 is internalized and showed the importance of the cytoplasmic juxtamembranal region in this process. The present study has identified the medium subunit (μ2) of adaptor protein 2 (AP-2) as a binding partner of KIAA0319 in a yeast two-hybrid screen. Using Rab5 mutants or depletion of the μ-subunit of AP-2 or clathrin heavy chain by RNA interference, we demonstrate that KIAA0319 follows a clathrin-mediated endocytic pathway. We also identify tyrosine-995 of KIAA0319 as a critical amino acid required for the interaction with AP-2 and subsequent internalization. These results suggest the surface expression of KIAA0319 is regulated by endocytosis, supporting the idea that the internalization and recycling of the protein may be involved in fine tuning its role in neuronal migration.

scholarly journals Regulation of Clathrin-Mediated Endocytosis

2018 ◽  
Vol 87 (1) ◽  
pp. 871-896 ◽  
Author(s):  
Marcel Mettlen ◽  
Ping-Hung Chen ◽  
Saipraveen Srinivasan ◽  
Gaudenz Danuser ◽  
Sandra L. Schmid
Keyword(s):  
Conformational Changes ◽  
Posttranslational Modifications ◽  
Mammalian Cells ◽  
Environmental Changes ◽  
Protein Complexes ◽  
Adaptor Protein ◽  
Endocytic Pathway ◽  
Coat Proteins ◽  
Membrane Composition ◽  
Coated Pits

Clathrin-mediated endocytosis (CME) is the major endocytic pathway in mammalian cells. It is responsible for the uptake of transmembrane receptors and transporters, for remodeling plasma membrane composition in response to environmental changes, and for regulating cell surface signaling. CME occurs via the assembly and maturation of clathrin-coated pits that concentrate cargo as they invaginate and pinch off to form clathrin-coated vesicles. In addition to the major coat proteins, clathrin triskelia and adaptor protein complexes, CME requires a myriad of endocytic accessory proteins and phosphatidylinositol lipids. CME is regulated at multiple steps—initiation, cargo selection, maturation, and fission—and is monitored by an endocytic checkpoint that induces disassembly of defective pits. Regulation occurs via posttranslational modifications, allosteric conformational changes, and isoform and splice-variant differences among components of the CME machinery, including the GTPase dynamin. This review summarizes recent findings on the regulation of CME and the evolution of this complex process.

scholarly journals Clustering of Nck by a 12-residue Tir phosphopeptide is sufficient to trigger localized actin assembly

2004 ◽  
Vol 164 (3) ◽  
pp. 407-416 ◽  
Author(s):  
Kenneth G. Campellone ◽  
Susannah Rankin ◽  
Tony Pawson ◽  
Marc W. Kirschner ◽  
Donald J. Tipper ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Adaptor Protein ◽  
Surface Expression ◽  
Effector Proteins ◽  
Actin Assembly ◽  
Filamentous Actin ◽  
Bacterial Surface ◽  
Egg Extracts ◽  
Xenopus Egg Extracts ◽  
Pedestal Formation

Enteropathogenic Escherichia coli (EPEC) translocates effector proteins into mammalian cells to promote reorganization of the cytoskeleton into filamentous actin pedestals. One effector, Tir, is a transmembrane receptor for the bacterial surface adhesin intimin, and intimin binding by the extracellular domain of Tir is required for actin assembly. The cytoplasmic NH2 terminus of Tir interacts with focal adhesion proteins, and its tyrosine-phosphorylated COOH terminus binds Nck, a host adaptor protein critical for pedestal formation. To define the minimal requirements for EPEC-mediated actin assembly, Tir derivatives were expressed in mammalian cells in the absence of all other EPEC components. Replacement of the NH2 terminus of Tir with a viral membrane-targeting sequence promoted efficient surface expression of a COOH-terminal Tir fragment. Artificial clustering of this fusion protein revealed that the COOH terminus of Tir, by itself, is sufficient to initiate a complete signaling cascade leading to pedestal formation. Consistent with this finding, clustering of Nck by a 12-residue Tir phosphopeptide triggered actin tail formation in Xenopus egg extracts.

scholarly journals Structure and mechanism of the human NHE1-CHP1 complex

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yanli Dong ◽  
Yiwei Gao ◽  
Alina Ilie ◽  
DuSik Kim ◽  
Annie Boucher ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Neurological Disorders ◽  
Mammalian Cells ◽  
Surface Expression ◽  
Ph Sensitivity ◽  
Cell Surface Expression ◽  
Transport Activity ◽  
Binding Partner ◽  
Homologous Protein ◽  
Calcineurin B

AbstractSodium/proton exchanger 1 (NHE1) is an electroneutral secondary active transporter present on the plasma membrane of most mammalian cells and plays critical roles in regulating intracellular pH and volume homeostasis. Calcineurin B-homologous protein 1 (CHP1) is an obligate binding partner that promotes NHE1 biosynthetic maturation, cell surface expression and pH-sensitivity. Dysfunctions of either protein are associated with neurological disorders. Here, we elucidate structures of the human NHE1-CHP1 complex in both inward- and inhibitor (cariporide)-bound outward-facing conformations. We find that NHE1 assembles as a symmetrical homodimer, with each subunit undergoing an elevator-like conformational change during cation exchange. The cryo-EM map reveals the binding site for the NHE1 inhibitor cariporide, illustrating how inhibitors block transport activity. The CHP1 molecule differentially associates with these two conformational states of each NHE1 monomer, and this association difference probably underlies the regulation of NHE1 pH-sensitivity by CHP1.

scholarly journals Functional Entry of Baculovirus into Insect and Mammalian Cells Is Dependent on Clathrin-Mediated Endocytosis

2006 ◽  
Vol 80 (17) ◽  
pp. 8830-8833 ◽  
Author(s):  
Gang Long ◽  
Xiaoyu Pan ◽  
Richard Kormelink ◽  
Just M. Vlak
Keyword(s):  
Electron Microscopy ◽  
Mammalian Cells ◽  
Low Ph ◽  
Coated Pits ◽  
Immuno Electron Microscopy ◽  
Endocytosis Pathway ◽  
Ph Dependent ◽  
Budded Virus

ABSTRACT Entry of the budded virus form of baculoviruses into insect and mammalian cells is generally thought to occur through a low-pH-dependent endocytosis pathway, possibly through clathrin-coated pits. This insight is primarily based on (immuno)electron microscopy studies but requires biochemical support to exclude the use of other pathways. Here, we demonstrate using various inhibitors that functional entry of baculoviruses into insect and mammalian cells is primarily dependent on clathrin-mediated endocytosis. Our results further suggest that caveolae are somehow involved in baculovirus entry in mammalian cells. A caveolar endocytosis inhibitor, genistein, enhances baculovirus transduction in these cells considerably.

A Role for Adaptor Protein-3 Complex in the Organization of the Endocytic Pathway in Dictyostelium

Traffic ◽  
2006 ◽  
Vol 7 (11) ◽  
pp. 1528-1538 ◽  
Author(s):  
Steve J. Charette ◽  
Valentina Mercanti ◽  
François Letourneur ◽  
Nelly Bennett ◽  
Pierre Cosson
Keyword(s):  
Adaptor Protein ◽  
Endocytic Pathway

scholarly journals The pro-oncogenic adaptor CIN85 inhibits hypoxia-inducible factor prolyl hydroxylase-2

2018 ◽  
Author(s):  
Nina Kozlova ◽  
Daniela Mennerich ◽  
Anatoly Samoylenko ◽  
Elitsa Y. Dimova ◽  
Peppi Koivunen ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Survival Function ◽  
Hypoxia Inducible Factor ◽  
Adaptor Protein ◽  
Prolyl Hydroxylase ◽  
Binding Partner ◽  
And Migration ◽  
Hif Prolyl Hydroxylase ◽  
Promote Breast Cancer

SummaryThe EGFR-adaptor protein CIN85 has been shown to promote breast cancer malignancy and hypoxia-inducible factor (HIF) stability. However, the mechanisms underlying cancer promotion remain ill-defined. Here, we show that CIN85 is a novel binding partner of the main HIF-prolyl hydroxylase PHD2, but not of PHD1 or PHD3. Mechanistically, the N-terminal SH3 domains of CIN85 interact with the proline-arginine rich region within the N-terminus of PHD2, thereby inhibiting PHD2 activity and HIF-degradation. This activity is essential in vivo, as specific loss of the CIN85-PHD2 interaction in CRISPR/Cas9 edited cells affected growth and migration properties as well as tumor growth in mice. Overall, we discovered a previously unrecognized tumor growth checkpoint that is regulated by CIN85-PHD2, and uncovered an essential survival function in tumor cells linking growth factor adaptors with hypoxia signaling.

scholarly journals Evasion of Intracellular DNA Sensing by Human Herpesviruses

2021 ◽  
Vol 11 ◽  
Author(s):  
Debipreeta Bhowmik ◽  
Fanxiu Zhu
Keyword(s):  
Immune Evasion ◽  
Mammalian Cells ◽  
Adaptor Protein ◽  
Large Family ◽  
Immune Defense ◽  
Dna Sensor ◽  
Dna Sensing ◽  
Dna Viruses ◽  
Sensor Degradation ◽  
Human Herpesviruses

Sensing of viral constituents is the first and critical step in the host innate immune defense against viruses. In mammalian cells, there are a variety of pathogen recognition receptors (PRRs) that detect diverse pathogen-associated molecular patterns (PAMPs) including viral RNA and DNA. In the past decade, a number of host DNA sensors have been discovered and the underlying sensing mechanisms have been elucidated. Herpesviruses belong to a large family of enveloped DNA viruses. They are successful pathogens whose elaborate immune evasion mechanisms contribute to high prevalence of infection among their hosts. The three subfamilies of herpesviruses have all been found to employ diverse and overlapping strategies to interfere with host DNA sensing. These strategies include masking viral DNA or the DNA sensor, degradation of the DNA sensor, and post-transcriptional modification of the DNA sensor or its adaptor protein. In this review, we will discuss the current state of our knowledge on how human herpesviruses use these strategies to evade DNA-induced immune responses. Comprehensive understanding of herpesvirus immune-evasion mechanisms will aid in the development of vaccines and antivirals for herpesvirus-associated diseases.

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