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[PMID]:28982131
[Au] Autor:Lu P; Li H; Li N; Singh RN; Bishop CE; Chen X; Lu B
[Ad] Endereço:Anhui Normal University, Wuhu, China.
[Ti] Título:MEX3C interacts with adaptor-related protein complex 2 and involves in miR-451a exosomal sorting.
[So] Source:PLoS One;12(10):e0185992, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Some RNA species, especially microRNAs, are non-randomly sorted into exosomes, but how selectivity of RNA exosomal sorting is achieved is unknown. We found that all three variants of RNA-binding ubiquitin E3 ligase (MEX3C)-MEX3C-1, MEX3C-2, and MEX3C-3 -interact with adaptor-related protein complex 2 (AP-2), a cargo adaptor in clathrin-mediated endocytosis. MEX3C's C-terminal RING finger domain and the hnRNP K homology (KH) domain shared by the three MEX3C variants are both necessary for MEX3C/AP-2 interaction. MEX3C associates with the endolysosomal compartment through an endocytosis-like process. siRNA-mediated inhibition of the MEX3C or AP-2 complex substantially decreased exosomal but not cellular microRNA miR-451a expression. Exosomal sorting is ceramide-dependent but not ESCRT-dependent in microRNA miR-451a. That RNA-binding protein associates with membrane trafficking machinery, and that its involvement in exosomal microRNA expression, suggest the existence of a mechanism for specific recruiting of RNA molecules to endosomes for subsequent exosomal sorting.
[Mh] Termos MeSH primário: Complexo 2 de Proteínas Adaptadoras/metabolismo
Exossomos/metabolismo
MicroRNAs/metabolismo
Proteínas de Ligação a RNA/metabolismo
[Mh] Termos MeSH secundário: Animais
Células HEK293
Seres Humanos
Camundongos
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Protein Complex 2); 0 (MEX3c protein, mouse); 0 (MicroRNAs); 0 (Mirn451 microRNA, mouse); 0 (RNA-Binding Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171006
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185992


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[PMID]:28855251
[Au] Autor:Fiuza M; Rostosky CM; Parkinson GT; Bygrave AM; Halemani N; Baptista M; Milosevic I; Hanley JG
[Ad] Endereço:Centre for Synaptic Plasticity and School of Biochemistry, University of Bristol, Bristol, England, UK.
[Ti] Título:PICK1 regulates AMPA receptor endocytosis via direct interactions with AP2 α-appendage and dynamin.
[So] Source:J Cell Biol;216(10):3323-3338, 2017 Oct 02.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Clathrin-mediated endocytosis (CME) is used to internalize a diverse range of cargo proteins from the cell surface, often in response to specific signals. In neurons, the rapid endocytosis of GluA2-containing AMPA receptors (AMPARs) in response to NMDA receptor (NMDAR) stimulation causes a reduction in synaptic strength and is the central mechanism for long-term depression, which underlies certain forms of learning. The mechanisms that link NMDAR activation to CME of AMPARs remain elusive. PICK1 is a BAR domain protein required for NMDAR-dependent reductions in surface GluA2; however, the molecular mechanisms involved are unclear. In this study, we show that PICK1 makes direct, NMDAR-dependent interactions with the core endocytic proteins AP2 and dynamin. PICK1-AP2 interactions are required for clustering AMPARs at endocytic zones in dendrites in response to NMDAR stimulation and for consequent AMPAR internalization. We further show that PICK1 stimulates dynamin polymerization. We propose that PICK1 is a cargo-specific endocytic accessory protein required for efficient, activity-dependent AMPAR endocytosis.
[Mh] Termos MeSH primário: Complexo 2 de Proteínas Adaptadoras/metabolismo
Proteínas de Transporte/metabolismo
Dinaminas/metabolismo
Endocitose/fisiologia
Proteínas Nucleares/metabolismo
Receptores de AMPA/metabolismo
Receptores de N-Metil-D-Aspartato/metabolismo
[Mh] Termos MeSH secundário: Complexo 2 de Proteínas Adaptadoras/genética
Animais
Proteínas de Transporte/genética
Dinaminas/genética
Células HEK293
Seres Humanos
Proteínas Nucleares/genética
Ratos
Ratos Wistar
Receptores de AMPA/genética
Receptores de N-Metil-D-Aspartato/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Protein Complex 2); 0 (Carrier Proteins); 0 (Nuclear Proteins); 0 (PICk1 protein, human); 0 (Prkcabp protein, rat); 0 (Receptors, AMPA); 0 (Receptors, N-Methyl-D-Aspartate); 0 (glutamate receptor ionotropic, AMPA 2); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201701034


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[PMID]:28577469
[Au] Autor:Jacob RA; Johnson AL; Pawlak EN; Dirk BS; Van Nynatten LR; Haeryfar SMM; Dikeakos JD
[Ad] Endereço:Department of Microbiology and Immunology, The University of Western Ontario, Schulich School of Medicine and Dentistry, London, Ontario, Canada.
[Ti] Título:The interaction between HIV-1 Nef and adaptor protein-2 reduces Nef-mediated CD4 T cell apoptosis.
[So] Source:Virology;509:1-10, 2017 Sep.
[Is] ISSN:1096-0341
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Acquired Immune Deficiency Syndrome is characterized by a decline in CD4 T cells. Here, we elucidated the mechanism underlying apoptosis in Human Immunodeficiency Virus-1 (HIV-1) infection by examining host apoptotic pathways hijacked by the HIV-1 Nef protein in the CD4 T-cell line Sup-T1. Using a panel of Nef mutants unable to bind specific host proteins we uncovered that Nef generates pro- and anti-apoptotic signals. Apoptosis increased upon mutating the motifs involved in the interaction of Nef:AP-1 (Nef or Nef ) or Nef:AP-2 (Nef ), implying these interactions limit Nef-mediated apoptosis. In contrast, disrupting the Nef:PAK2 interaction motifs (Nef or Nef ) reduced apoptosis. To validate further, apoptosis was measured after short-hairpin RNA knock-down of AP-1, AP-2 and PAK2. AP-2α depletion enhanced apoptosis, demonstrating that disrupting the Nef:AP-2α interaction limits Nef-mediated apoptosis. Collectively, we describe a mechanism by which HIV-1 regulates cell survival and demonstrate the consequence of interfering with Nef:host protein interactions.
[Mh] Termos MeSH primário: Complexo 2 de Proteínas Adaptadoras/metabolismo
Apoptose
Linfócitos T CD4-Positivos/fisiologia
Linfócitos T CD4-Positivos/virologia
HIV-1/patogenicidade
Interações Hospedeiro-Patógeno
Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular
Análise Mutacional de DNA
Seres Humanos
Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Protein Complex 2); 0 (nef Gene Products, Human Immunodeficiency Virus); 0 (nef protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170721
[Lr] Data última revisão:
170721
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170604
[St] Status:MEDLINE


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[PMID]:28240606
[Au] Autor:Bekerman E; Neveu G; Shulla A; Brannan J; Pu SY; Wang S; Xiao F; Barouch-Bentov R; Bakken RR; Mateo R; Govero J; Nagamine CM; Diamond MS; De Jonghe S; Herdewijn P; Dye JM; Randall G; Einav S
[Ti] Título:Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects.
[So] Source:J Clin Invest;127(4):1338-1352, 2017 Apr 03.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Global health is threatened by emerging viral infections, which largely lack effective vaccines or therapies. Targeting host pathways that are exploited by multiple viruses could offer broad-spectrum solutions. We previously reported that AAK1 and GAK, kinase regulators of the host adaptor proteins AP1 and AP2, are essential for hepatitis C virus (HCV) infection, but the underlying mechanism and relevance to other viruses or in vivo infections remained unknown. Here, we have discovered that AP1 and AP2 cotraffic with HCV particles in live cells. Moreover, we found that multiple viruses, including dengue and Ebola, exploit AAK1 and GAK during entry and infectious virus production. In cultured cells, treatment with sunitinib and erlotinib, approved anticancer drugs that inhibit AAK1 or GAK activity, or with more selective compounds inhibited intracellular trafficking of HCV and multiple unrelated RNA viruses with a high barrier to resistance. In murine models of dengue and Ebola infection, sunitinib/erlotinib combination protected against morbidity and mortality. We validated sunitinib- and erlotinib-mediated inhibition of AAK1 and GAK activity as an important mechanism of antiviral action. Additionally, we revealed potential roles for additional kinase targets. These findings advance our understanding of virus-host interactions and establish a proof of principle for a repurposed, host-targeted approach to combat emerging viruses.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Antivirais/farmacologia
Cloridrato de Erlotinib/farmacologia
Indóis/farmacologia
Inibidores de Proteínas Quinases/farmacologia
Pirróis/farmacologia
[Mh] Termos MeSH secundário: Complexo 1 de Proteínas Adaptadoras/metabolismo
Complexo 2 de Proteínas Adaptadoras/metabolismo
Animais
Linhagem Celular Tumoral
Dengue/prevenção & controle
Dengue/virologia
Vírus da Dengue/efeitos dos fármacos
Vírus da Dengue/metabolismo
Avaliação Pré-Clínica de Medicamentos
Sinergismo Farmacológico
Ebolavirus/efeitos dos fármacos
Ebolavirus/metabolismo
Feminino
Doença pelo Vírus Ebola/prevenção & controle
Doença pelo Vírus Ebola/virologia
Hepacivirus/efeitos dos fármacos
Hepacivirus/metabolismo
Hepatite C/prevenção & controle
Hepatite C/virologia
Seres Humanos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Masculino
Camundongos da Linhagem 129
Camundongos Endogâmicos C57BL
Transporte Proteico
Proteínas Serina-Treonina Quinases/antagonistas & inibidores
Proteínas Serina-Treonina Quinases/metabolismo
Internalização do Vírus/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Protein Complex 1); 0 (Adaptor Protein Complex 2); 0 (Antineoplastic Agents); 0 (Antiviral Agents); 0 (Indoles); 0 (Intracellular Signaling Peptides and Proteins); 0 (Protein Kinase Inhibitors); 0 (Pyrroles); DA87705X9K (Erlotinib Hydrochloride); EC 2.7.11.1 (AAK1 protein, human); EC 2.7.11.1 (GAK protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); V99T50803M (sunitinib)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170228
[St] Status:MEDLINE


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[PMID]:28232524
[Au] Autor:Manna PT; Obado SO; Boehm C; Gadelha C; Sali A; Chait BT; Rout MP; Field MC
[Ad] Endereço:School of Life Sciences, University of Dundee, Dundee, Scotland DD1 5EH, UK.
[Ti] Título:Lineage-specific proteins essential for endocytosis in trypanosomes.
[So] Source:J Cell Sci;130(8):1379-1392, 2017 Apr 15.
[Is] ISSN:1477-9137
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Clathrin-mediated endocytosis (CME) is the most evolutionarily ancient endocytic mechanism known, and in many lineages the sole mechanism for internalisation. Significantly, in mammalian cells CME is responsible for the vast bulk of endocytic flux and has likely undergone multiple adaptations to accommodate specific requirements by individual species. In African trypanosomes, we previously demonstrated that CME is independent of the AP-2 adaptor protein complex, that orthologues to many of the animal and fungal CME protein cohort are absent, and that a novel, trypanosome-restricted protein cohort interacts with clathrin and drives CME. Here, we used a novel cryomilling affinity isolation strategy to preserve transient low-affinity interactions, giving the most comprehensive trypanosome clathrin interactome to date. We identified the trypanosome AP-1 complex, (Tb)EpsinR, several endosomal SNAREs plus orthologues of SMAP and the AP-2 associated kinase AAK1 as interacting with clathrin. Novel lineage-specific proteins were identified, which we designate TbCAP80 and TbCAP141. Their depletion produced extensive defects in endocytosis and endomembrane system organisation, revealing a novel molecular pathway subtending an early-branching and highly divergent form of CME, which is conserved and likely functionally important across the kinetoplastid parasites.
[Mh] Termos MeSH primário: Endocitose
Trypanosoma brucei brucei
Tripanossomíase/metabolismo
[Mh] Termos MeSH secundário: Complexo 2 de Proteínas Adaptadoras/metabolismo
Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Proteínas Adaptadoras de Transporte Vesicular/metabolismo
Animais
Evolução Biológica
Clatrina/metabolismo
Proteínas do Citoesqueleto/metabolismo
Seres Humanos
Filogenia
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas de Protozoários/metabolismo
Proteínas SNARE/metabolismo
Fator de Transcrição AP-1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Protein Complex 2); 0 (Adaptor Proteins, Signal Transducing); 0 (Adaptor Proteins, Vesicular Transport); 0 (CLINT1 protein, human); 0 (Clathrin); 0 (Cytoskeletal Proteins); 0 (KIFAP3 protein, human); 0 (Protozoan Proteins); 0 (SNARE Proteins); 0 (Transcription Factor AP-1); EC 2.7.11.1 (AAK1 protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170518
[Lr] Data última revisão:
170518
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE
[do] DOI:10.1242/jcs.191478


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[PMID]:28176280
[Au] Autor:Szalat A; Shpitzen S; Tsur A; Zalmon Koren I; Shilo S; Tripto-Shkolnik L; Durst R; Leitersdorf E; Meiner V
[Ad] Endereço:Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. auryans@hadassah.org.il.
[Ti] Título:Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia.
[So] Source:Endocrine;55(3):741-747, 2017 Mar.
[Is] ISSN:1559-0100
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Patients with familial hyperparathyroidism and low urinary calcium excretion may have familial hypocalciuric hypercalcemia (FHH) with mutations in one of three genes: the calcium-sensing receptor (CaSR) defining FHH-type 1, the adaptor-related protein complex 2 (AP2S1) related to FHH-type 3 or the G-protein subunit alpha11 (GNA11) associated with FHH-type 2. We aimed to evaluate the presence of mutations in these genes and to identify phenotypic specificities and differences in these patients. SUBJECTS AND METHODS: Selected patients were recruited for genetic evaluation. After informed consent was signed, blood for DNA extraction was obtained and genetic sequencing of CaSR was done. In negative cases, we further performed sequencing of AP2S1 and GNA11. RESULTS: A total of 10 index cases were recruited. CaSR sequencing yielded three missense heterozygous mutations (30%): c.554G > A (p.I32V) previously characterized by our team, c.1394 G > A (p.R465Q) and a novel expected disease-causing mutation c.2479 A > C (p.S827R). We identified 2 additional patients (20%) carrying the deleterious recurrent mutation c.44G > T (p.R15L) in the AP2S1 gene. No GNA11 mutation was found. Clinically, patients with AP2S1 mutations had significant cognitive and behavioral disorders, and higher blood calcium and magnesium levels than patients with FHH1. CONCLUSION: CaSR and AP2S1 sequencing is worthwhile in patients with familial hyperparathyroidism and phenotype suggesting FHH as it can diagnose up to 50% of cases. GNA11 mutations seem much rarer. Learning disabilities in these patients, associated with higher serum calcium and magnesium levels may suggest the presence of AP2S1 rather than CaSR mutation and may guide the first step in the genetic evaluation.
[Mh] Termos MeSH primário: Complexo 2 de Proteínas Adaptadoras/genética
Subunidades sigma do Complexo de Proteínas Adaptadoras/genética
Subunidades alfa de Proteínas de Ligação ao GTP/genética
Hipercalcemia/congênito
Mutação
Receptores de Detecção de Cálcio/genética
[Mh] Termos MeSH secundário: Adulto
Pré-Escolar
Feminino
Seres Humanos
Hipercalcemia/diagnóstico
Hipercalcemia/genética
Recém-Nascido
Masculino
Análise de Sequência com Séries de Oligonucleotídeos
Linhagem
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AP2S1 protein, human); 0 (Adaptor Protein Complex 2); 0 (Adaptor Protein Complex sigma Subunits); 0 (CASR protein, human); 0 (GNA11 protein, human); 0 (GTP-Binding Protein alpha Subunits); 0 (Receptors, Calcium-Sensing)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170209
[St] Status:MEDLINE
[do] DOI:10.1007/s12020-017-1241-5


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[PMID]:28003333
[Au] Autor:Kadlecova Z; Spielman SJ; Loerke D; Mohanakrishnan A; Reed DK; Schmid SL
[Ad] Endereço:Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
[Ti] Título:Regulation of clathrin-mediated endocytosis by hierarchical allosteric activation of AP2.
[So] Source:J Cell Biol;216(1):167-179, 2017 Jan 02.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The critical initiation phase of clathrin-mediated endocytosis (CME) determines where and when endocytosis occurs. Heterotetrameric adaptor protein 2 (AP2) complexes, which initiate clathrin-coated pit (CCP) assembly, are activated by conformational changes in response to phosphatidylinositol-4,5-bisphosphate (PIP2) and cargo binding at multiple sites. However, the functional hierarchy of interactions and how these conformational changes relate to distinct steps in CCP formation in living cells remains unknown. We used quantitative live-cell analyses to measure discrete early stages of CME and show how sequential, allosterically regulated conformational changes activate AP2 to drive both nucleation and subsequent stabilization of nascent CCPs. Our data establish that cargoes containing Yxxφ motif, but not dileucine motif, play a critical role in the earliest stages of AP2 activation and CCP nucleation. Interestingly, these cargo and PIP2 interactions are not conserved in yeast. Thus, we speculate that AP2 has evolved as a key regulatory node to coordinate CCP formation and cargo sorting and ensure high spatial and temporal regulation of CME.
[Mh] Termos MeSH primário: Complexo 2 de Proteínas Adaptadoras/metabolismo
Vesículas Revestidas por Clatrina/metabolismo
Clatrina/metabolismo
Invaginações Revestidas da Membrana Celular/metabolismo
Endocitose
Epitélio Pigmentado da Retina/metabolismo
[Mh] Termos MeSH secundário: Complexo 2 de Proteínas Adaptadoras/química
Complexo 2 de Proteínas Adaptadoras/genética
Subunidades alfa do Complexo de Proteínas Adaptadoras/genética
Subunidades alfa do Complexo de Proteínas Adaptadoras/metabolismo
Subunidades mu do Complexo de Proteínas Adaptadoras/genética
Subunidades mu do Complexo de Proteínas Adaptadoras/metabolismo
Motivos de Aminoácidos
Linhagem Celular
Seres Humanos
Fosfatidilinositol 4,5-Difosfato/metabolismo
Ligação Proteica
Conformação Proteica
Estabilidade Proteica
Transporte Proteico
Proteínas Serina-Treonina Quinases/metabolismo
Interferência de RNA
Transdução de Sinais
Relação Estrutura-Atividade
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Protein Complex 2); 0 (Adaptor Protein Complex alpha Subunits); 0 (Adaptor Protein Complex mu Subunits); 0 (Clathrin); 0 (Phosphatidylinositol 4,5-Diphosphate); 0 (adaptor protein complex 2, alpha 2 subunit); 0 (adaptor protein complex 2, mu 1 subunit); EC 2.7.11.1 (AAK1 protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161223
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201608071


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[PMID]:27980069
[Au] Autor:Jastrzebski K; Zdzalik-Bielecka D; Maminska A; Kalaidzidis Y; Hellberg C; Miaczynska M
[Ad] Endereço:Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Warsaw 02-109, Poland.
[Ti] Título:Multiple routes of endocytic internalization of PDGFRß contribute to PDGF-induced STAT3 signaling.
[So] Source:J Cell Sci;130(3):577-589, 2017 Feb 01.
[Is] ISSN:1477-9137
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Platelet-derived growth factor receptor ß (PDGFRß) is a receptor tyrosine kinase which upon activation by PDGF-BB stimulates cell proliferation, migration and angiogenesis. Ligand binding induces intracellular signaling cascades but also internalization of the receptor, eventually resulting in its lysosomal degradation. However, endocytic trafficking of receptors often modulates their downstream signaling. We previously reported that internalization of PDGFRß occurs via dynamin-dependent and -independent pathways but their further molecular determinants remained unknown. Here we show that, in human fibroblasts expressing endogenous PDGFRß and stimulated with 50 ng/ml PDGF-BB, ligand-receptor uptake proceeds via the parallel routes of clathrin-mediated endocytosis (CME) and clathrin-independent endocytosis (CIE). CME involves the canonical AP2 complex as a clathrin adaptor, while CIE requires RhoA-ROCK, Cdc42 and galectin-3, the latter indicating lectin-mediated internalization via clathrin-independent carriers (CLICs). Although different uptake routes appear to be partly interdependent, they cannot fully substitute for each other. Strikingly, inhibition of any internalization mechanism impaired activation of STAT3 but not of other downstream effectors of PDGFRß. Our data indicate that multiple routes of internalization of PDGFRß contribute to a transcriptional and mitogenic response of cells to PDGF.
[Mh] Termos MeSH primário: Endocitose/efeitos dos fármacos
Fator de Crescimento Derivado de Plaquetas/farmacologia
Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo
Fator de Transcrição STAT3/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Complexo 2 de Proteínas Adaptadoras/metabolismo
Clatrina/metabolismo
DNA/biossíntese
Dinaminas/metabolismo
Endocitose/genética
Galectina 3/metabolismo
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Receptores de Hialuronatos/metabolismo
Masculino
Transdução de Sinais/genética
Transcrição Genética/efeitos dos fármacos
Proteína cdc42 de Ligação ao GTP/metabolismo
Proteínas rac1 de Ligação ao GTP/metabolismo
Quinases Associadas a rho/metabolismo
Proteína rhoA de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Protein Complex 2); 0 (Clathrin); 0 (Galectin 3); 0 (Hyaluronan Receptors); 0 (Platelet-Derived Growth Factor); 0 (STAT3 Transcription Factor); 9007-49-2 (DNA); EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor beta); EC 2.7.11.1 (rho-Associated Kinases); EC 3.6.5.2 (cdc42 GTP-Binding Protein); EC 3.6.5.2 (rac1 GTP-Binding Protein); EC 3.6.5.2 (rhoA GTP-Binding Protein); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161217
[St] Status:MEDLINE
[do] DOI:10.1242/jcs.191213


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[PMID]:27974503
[Au] Autor:Hoya M; Yanguas F; Moro S; Prescianotto-Baschong C; Doncel C; de León N; Curto MÁ; Spang A; Valdivieso MH
[Ad] Endereço:Department of Microbiology and Genetics, Institute of Functional Biology and Genomics (IBFG), University of Salamanca, Consejo Superior de Investigaciones Científicas (CSIC), 37007, Spain.
[Ti] Título:Traffic Through the Trans-Golgi Network and the Endosomal System Requires Collaboration Between Exomer and Clathrin Adaptors in Fission Yeast.
[So] Source:Genetics;205(2):673-690, 2017 Feb.
[Is] ISSN:1943-2631
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Despite its biological and medical relevance, traffic from the Golgi to the plasma membrane (PM) is one of the least understood steps of secretion. Exomer is a protein complex that mediates the trafficking of certain cargoes from the trans-Golgi network/early endosomes to the PM in budding yeast. Here, we show that in Schizosaccharomyces pombe the Cfr1 and Bch1 proteins constitute the simplest form of an exomer. Cfr1 co-immunoprecipitates with Assembly Polypeptide adaptor 1 (AP-1), AP-2, and Golgi-localized, gamma-adaptin ear domain homology, ARF-binding (GGA) subunits, and cfr1 interacts genetically with AP-1 and GGA genes. Exomer-defective cells exhibit multiple mild defects, including alterations in the morphology of Golgi stacks and the distribution of the synaptobrevin-like Syb1 protein, carboxypeptidase missorting, and stress sensitivity. S. pombe apm1Δ cells exhibit a defect in trafficking through the early endosomes that is severely aggravated in the absence of exomer. apm1Δ cfr1Δ cells exhibit a dramatic disorganization of intracellular compartments, including massive accumulation of electron-dense tubulovesicular structures. While the trans-Golgi network/early endosomes are severely disorganized in the apm1Δ cfr1Δ strain, gga21Δ gga22Δ cfr1Δ cells exhibit a significant disturbance of the prevacuolar/vacuolar compartments. Our findings show that exomer collaborates with clathrin adaptors in trafficking through diverse cellular compartments, and that this collaboration is important to maintain their integrity. These results indicate that the effect of eliminating exomer is more pervasive than that described to date, and suggest that exomer complexes might participate in diverse steps of vesicle transport in other organisms.
[Mh] Termos MeSH primário: Complexo 1 de Proteínas Adaptadoras/metabolismo
Complexo 2 de Proteínas Adaptadoras/metabolismo
Proteínas Adaptadoras de Transporte Vesicular/genética
Endossomos/metabolismo
Proteínas de Schizosaccharomyces pombe/genética
Schizosaccharomyces/metabolismo
Rede trans-Golgi/metabolismo
[Mh] Termos MeSH secundário: Complexo 1 de Proteínas Adaptadoras/genética
Complexo 2 de Proteínas Adaptadoras/genética
Proteínas Adaptadoras de Transporte Vesicular/metabolismo
Ligação Proteica
Transporte Proteico
Proteínas R-SNARE/genética
Proteínas R-SNARE/metabolismo
Schizosaccharomyces/genética
Proteínas de Schizosaccharomyces pombe/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Protein Complex 1); 0 (Adaptor Protein Complex 2); 0 (Adaptor Proteins, Vesicular Transport); 0 (R-SNARE Proteins); 0 (Schizosaccharomyces pombe Proteins); 0 (Syb1 protein, S pombe); 0 (cfr1 protein, S pombe)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170530
[Lr] Data última revisão:
170530
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161216
[St] Status:MEDLINE
[do] DOI:10.1534/genetics.116.193458


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[PMID]:27913609
[Au] Autor:Hovden S; Rejnmark L; Ladefoged SA; Nissen PH
[Ad] Endereço:Departments of Clinical Biochemistry.
[Ti] Título:AP2S1 and GNA11 mutations - not a common cause of familial hypocalciuric hypercalcemia.
[So] Source:Eur J Endocrinol;176(2):177-185, 2017 Feb.
[Is] ISSN:1479-683X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Familial hypocalciuric hypercalcemia (FHH) type 1 is caused by mutations in the gene encoding the calcium-sensing receptor (CASR). Recently, mutations affecting codon 15 in the gene AP2S1 have been shown to cause FHH type 3 in up to 26% of CASR-negative FHH patients. Similarly, mutations in the gene GNA11 have been shown to cause FHH type 2. We hypothesized that mutations in AP2S1 and GNA11 are causative in Danish patients with suspected FHH and that these mutations are not found in patients with primary hyperparathyroidism (PHPT), which is the main differential diagnostic disorder. DESIGN: Cross-sectional study. METHODS: We identified patients with unexplained hyperparathyroid hypercalcemia and a control group of verified PHPT patients through review of 421 patients tested for CASR mutations in the period 2006-2014. DNA sequencing of all amino acid coding exons including intron-exon boundaries in AP2S1 and GNA11 was performed. RESULTS: In 33 CASR-negative patients with suspected FHH, we found two (~6%) with a mutation in AP2S1 (p.Arg15Leu and p.Arg15His). Family screening confirmed the genotype-phenotype correlations. We did not identify any pathogenic mutations in GNA11. No pathogenic mutations were found in the PHPT control group. CONCLUSIONS: We suggest that the best diagnostic approach to hyperparathyroid hypercalcemic patients suspected to have FHH is to screen the CASR and AP2S1 codon 15 for mutations. If the results are negative and there is still suspicion of an inherited condition (i.e. family history), then GNA11 should be examined.
[Mh] Termos MeSH primário: Complexo 2 de Proteínas Adaptadoras/genética
Subunidades sigma do Complexo de Proteínas Adaptadoras/genética
Subunidades alfa de Proteínas de Ligação ao GTP/genética
Hipercalcemia/congênito
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Cálcio/metabolismo
Estudos Transversais
Seres Humanos
Hipercalcemia/genética
Meia-Idade
Mutação
Hormônio Paratireóideo/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AP2S1 protein, human); 0 (Adaptor Protein Complex 2); 0 (Adaptor Protein Complex sigma Subunits); 0 (GNA11 protein, human); 0 (GTP-Binding Protein alpha Subunits); 0 (Parathyroid Hormone); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170207
[Lr] Data última revisão:
170207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161204
[St] Status:MEDLINE



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