scholarly journals Rab11fip5 regulates telencephalon development via ephrinB1 recycling

Development ◽  
2021 ◽  
Vol 148 (3) ◽  
pp. dev196527
Author(s):  
Jaeho Yoon ◽  
Jerlin Garo ◽  
Moonsup Lee ◽  
Jian Sun ◽  
Yoo-Seok Hwang ◽  
...  
Keyword(s):  
Iron Uptake ◽  
Adaptor Protein ◽  
Autism Spectrum ◽  
Small Gtpase ◽  
Neuroendocrine Cells ◽  
Binding Motif ◽  
Eph Receptors ◽  
Interacting Protein ◽  
Cellular Processes

ABSTRACTRab11 family-interacting protein 5 (Rab11fip5) is an adaptor protein that binds to the small GTPase Rab11, which has an important function in endosome recycling and trafficking of cellular proteins to the plasma membrane. Rab11fip5 is involved in many cellular processes, such as cytoskeleton rearrangement, iron uptake and exocytosis in neuroendocrine cells, and is also known as a candidate gene for autism-spectrum disorder. However, the role of Rab11fip5 during early embryonic development is not clearly understood. In this study, we identified Rab11fip5 as a protein that interacts with ephrinB1, a transmembrane ligand for Eph receptors. The PDZ binding motif in ephrinB1 and the Rab-binding domain in Rab11fip5 are necessary for their interaction in a complex. EphrinB1 and Rab11fip5 display overlapping expression in the telencephalon of developing amphibian embryos. The loss of Rab11fip5 function causes a reduction in telencephalon size and a decrease in the expression level of ephrinB1. Moreover, morpholino oligonucleotide-mediated knockdown of Rab11fip5 decreases cell proliferation in the telencephalon. The overexpression of ephrinB1 rescues these defects, suggesting that ephrinB1 recycling by the Rab11/Rab11fip5 complex is crucial for proper telencephalon development.

scholarly journals Identification of Tetratricopeptide Repeat 1 as an Adaptor Protein That Interacts with Heterotrimeric G Proteins and the Small GTPase Ras

2003 ◽  
Vol 23 (11) ◽  
pp. 3847-3858 ◽  
Author(s):  
Caroline Marty ◽  
Darren D. Browning ◽  
Richard D. Ye
Keyword(s):  
G Proteins ◽  
Mammalian Cells ◽  
Active Form ◽  
Adaptor Protein ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Tetratricopeptide Repeat ◽  
Heterotrimeric G Proteins ◽  
Interacting Protein

ABSTRACT The biological functions of heterotrimeric G proteins and small GTPases are modulated by both extracellular stimuli and intracellular regulatory proteins. Using Saccharomyces cerevisiae two-hybrid screening, we identified tetratricopeptide repeat 1 (TPR1), a 292-amino-acid protein with three TPR motifs, as a Gα16-binding protein. The interaction was confirmed both in vitro and in transfected mammalian cells, where TPR1 also binds to several other Gα proteins. TPR1 was found to interact with Ha-Ras preferentially in its active form. Overexpression of TPR1 promotes accumulation of active Ras. TPR1 was found to compete with the Ras-binding domain (RBD) of Raf-1 for binding to the active Ras, suggesting that it may also compete with Ras GTPase-activating protein, thus contributing to the accumulation of GTP-bound Ras. Expression of Gα16 strongly enhances the interaction between TPR1 and Ras. Removal of the TPR1 N-terminal 112 residues abolishes potentiation by Gα16 while maintaining the interaction with Gα16 and the ability to discriminate active Ras from wild-type Ras. We have also observed that LGN, a Gαi-interacting protein with seven TPR motifs, binds Ha-Ras. Thus, TPR1 is a novel adaptor protein for Ras and selected Gα proteins that may be involved in protein-protein interaction relating to G-protein signaling.

scholarly journals Role of Toll-Interacting Protein Gene Polymorphisms in Leprosy Mexican Patients

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Margarita Montoya-Buelna ◽  
Mary Fafutis-Morris ◽  
Alvaro J. Tovar-Cuevas ◽  
Anabell Alvarado-Navarro ◽  
Yeminia Valle ◽  
...  
Keyword(s):  
Adaptor Protein ◽  
Lepromatous Leprosy ◽  
Microbial Pathogens ◽  
Specific Primers ◽  
Interacting Protein ◽  
Hardy Weinberg Equilibrium ◽  
Genotype C ◽  
Molecular Patterns ◽  
Mexican Patients

Background. Leprosy is a debilitating infectious disease of human skin and nerves. Genetics factors of the host play an important role in the disease susceptibility. Toll-interacting protein (TOLLIP) is an inhibitory adaptor protein within the toll-like receptor (TLR) pathway, which recognizes structurally conserved molecular patterns of microbial pathogens, initiating immune responses. The objective of this study was to investigate the association of variants in theTOLLIPgene with susceptibility to leprosy in Mexican patients.Methods.TOLLIPpolymorphisms were studied using a case-control design of Mexican patients with lepromatous leprosy (LL). The polymorphisms ofTOLLIPat loci −526 C>G (rs5743854), 1309956C>T (rs3750920), 1298430C>A (rs5744015), and 1292831 G>A (rs3750919) were analyzed by PCR, with sequence-specific primers in LL patients and healthy subjects (HS) as controls.Results. Genotype distributions were in Hardy Weinberg equilibrium for all sites except for rs3750920. Neither genotype nor allele frequencies were statistically different between LL patients and controls (P>0.05). The maximum pairwise D’ coefficient reached was 0.44 of linkage (P=0.01) for all the polymorphisms except for rs5743854. The three loci haplotype comparison yielded no significant differences between groups.Conclusions. Just the individuals with genotype C/C of rs3750920 have a trend of protective effect to developing LL.

scholarly journals Pathogenic mutations in LRRK2 sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia

2020 ◽  
Author(s):  
Adamantios Mamais ◽  
Natalie Landeck ◽  
Rebekah G. Langston ◽  
Luis Bonet-Ponce ◽  
Nathan Smith ◽  
...  
Keyword(s):  
Iron Uptake ◽  
Kinase Activity ◽  
Small Gtpase ◽  
Kinase Substrate ◽  
Lrrk2 Kinase ◽  
Effect Of Pd ◽  
Lrrk2 Kinase Activity

AbstractMutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson’s disease (PD) while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a are poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a into lysosomes in cells while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive accumulation of endocytosed transferrin into Rab8a-positive lysosomes leading to a dysregulation of iron transport. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in post-mortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia.

scholarly journals The PDZ-adaptor protein syntenin-1 regulates HIV-1 entry

2012 ◽  
Vol 23 (12) ◽  
pp. 2253-2263 ◽  
Author(s):  
Mónica Gordón-Alonso ◽  
Vera Rocha-Perugini ◽  
Susana Álvarez ◽  
Olga Moreno-Gonzalo ◽  
Ángeles Ursa ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Adaptor Protein ◽  
Viral Receptor ◽  
Actin Remodeling ◽  
Cellular Processes ◽  
Immunodeficiency Virus ◽  
Viral Nucleocapsid ◽  
Hiv 1

Syntenin-1 is a cytosolic adaptor protein involved in several cellular processes requiring polarization. Human immunodeficiency virus type 1 (HIV-1) attachment to target CD4+T-cells induces polarization of the viral receptor and coreceptor, CD4/CXCR4, and cellular structures toward the virus contact area, and triggers local actin polymerization and phosphatidylinositol 4,5-bisphosphate (PIP2) production, which are needed for successful HIV infection. We show that syntenin-1 is recruited to the plasma membrane during HIV-1 attachment and associates with CD4, the main HIV-1 receptor. Syntenin-1 overexpression inhibits HIV-1 production and HIV-mediated cell fusion, while syntenin depletion specifically increases HIV-1 entry. Down-regulation of syntenin-1 expression reduces F-actin polymerization in response to HIV-1. Moreover, HIV-induced PIP2accumulation is increased in syntenin-1–depleted cells. Once the virus has entered the target cell, syntenin-1 polarization toward the viral nucleocapsid is lost, suggesting a spatiotemporal regulatory role of syntenin-1 in actin remodeling, PIP2production, and the dynamics of HIV-1 entry.

scholarly journals Tuning of in vivo cognate B-T cell interactions by Intersectin 2 is required for effective anti-viral B cell immunity

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Marianne Burbage ◽  
Francesca Gasparrini ◽  
Shweta Aggarwal ◽  
Mauro Gaya ◽  
Johan Arnold ◽  
...  
Keyword(s):  
B Cell ◽  
Adaptive Immune Response ◽  
Adaptor Protein ◽  
Small Gtpase ◽  
Germinal Centre ◽  
Nucleotide Exchange ◽  
Interacting Protein ◽  
Flu Vaccination ◽  
Cell Immunity

Wiskott-Aldrich syndrome (WAS) is an immune pathology associated with mutations in WAS protein (WASp) or in WASp interacting protein (WIP). Together with the small GTPase Cdc42 and other effectors, these proteins participate in the remodelling of the actin network downstream of BCR engagement. Here we show that mice lacking the adaptor protein ITSN2, a G-nucleotide exchange factor (GEF) for Cdc42 that also interacts with WASp and WIP, exhibited increased mortality during primary infection, incomplete protection after Flu vaccination, reduced germinal centre formation and impaired antibody responses to vaccination. These defects were found, at least in part, to be intrinsic to the B cell compartment. In vivo, ITSN2 deficient B cells show a reduction in the expression of SLAM, CD84 or ICOSL that correlates with a diminished ability to form long term conjugates with T cells, to proliferate in vivo, and to differentiate into germinal centre cells. In conclusion, our study not only revealed a key role for ITSN2 as an important regulator of adaptive immune-response during vaccination and viral infection but it is also likely to contribute to a better understanding of human immune pathologies.

scholarly journals Involvement of PDZ-SAP97 interactions in regulating AQP2 translocation in response to vasopressin in LLC-PK1 cells

2019 ◽  
Vol 317 (2) ◽  
pp. F375-F387 ◽  
Author(s):  
Mohammed M. Nooh ◽  
Ajay Kale ◽  
Suleiman W. Bahouth
Keyword(s):  
Binding Motif ◽  
Interacting Protein ◽  
Binding Partner ◽  
Storage Vesicles ◽  
Protein Partners ◽  
Cell Surface Biotinylation ◽  
Collecting Ducts ◽  
Precise Role

Arginine-vasopressin (AVP)-mediated translocation of aquaporin-2 (AQP2) protein-forming water channels from storage vesicles to the membrane of renal collecting ducts is critical for the renal conservation of water. The type-1 PDZ-binding motif (PBM) in AQP2, “GTKA,” is a critical barcode for its translocation, but its precise role and that of its interacting protein partners in this process remain obscure. We determined that synapse-associated protein-97 (SAP97), a membrane-associated guanylate kinase protein involved in establishing epithelial cell polarity, was an avid binding partner to the PBM of AQP2. The role of PBM and SAP97 on AQP2 redistribution in response to AVP was assessed in LLC-PK1 renal collecting cells by confocal microscopy and cell surface biotinylation techniques. These experiments indicated that distribution of AQP2 and SAP97 overlapped in the kidneys and LLC-PK1 cells and that knockdown of SAP97 inhibited the translocation of AQP2 in response to AVP. Binding between AQP2 and SAP97 was mediated by specific interactions between the second PDZ of SAP97 and PBM of AQP2. Mechanistically, inactivation of the PBM of AQP2, global delocalization of PKA, or knockdown of SAP97 inhibited AQP2 translocation as well as AVP- and forskolin-mediated phosphorylation of Ser256 in AQP2, which serves as the major translocation barcode of AQP2. These results suggest that the targeting of PKA to the microdomain of AQP2 via SAP97-AQP2 interactions in association with cross-talk between two barcodes in AQP2, namely, the PBM and phospho-Ser256, plays an important role in the translocation of AQP2 in the kidney.

Differential distribution of mannose-6-phosphate receptors and furin in immature secretory granules

1999 ◽  
Vol 112 (22) ◽  
pp. 3955-3966 ◽  
Author(s):  
A.S. Dittie ◽  
J. Klumperman ◽  
S.A. Tooze
Keyword(s):  
Fusion Proteins ◽  
Secretory Granules ◽  
Adaptor Protein ◽  
Subcellular Fractionation ◽  
Neuroendocrine Cells ◽  
Differential Distribution ◽  
A Cell ◽  
Mannose 6 Phosphate ◽  
The Relationship

In neuroendocrine cells sorting of proteins from immature secretory granules (ISGs) occurs during maturation and is achieved by clathrin-coated vesicles containing the adaptor protein (AP)-1. We have investigated the role of the mannose-6-phosphate receptors (M6PRs) in the recruitment of AP-1 to ISGs. M6PRs were detected in ISGs isolated from PC12 cells by subcellular fractionation, and by immuno-EM labelling on cryosections. In light of our previous results, where greater than 80% of the ISGs were found to contain furin, we examined the relationship between furin and M6PR on ISGs. By immunoisolation techniques we find that 50% at most of the ISGs contain the cation-independent (CI)-M6PR. Using sequential immunoisolation we could demonstrate that there are two populations of ISGs: those that have both M6PR and furin, and those which contain only furin. Furthermore, using immobilized GST-fusion proteins containing the cytoplasmic domain of the CI-M6PR we have shown binding of AP-1 requires casein kinase II phosphorylation of the CI-M6PR fusion protein, and in particular phosphorylation of Ser(2474). Addition of these phosphorylated GST-CI-M6PR fusion proteins to a cell-free assay reconstituting AP-1 binding to ISGs inhibits AP-1 recruitment to ISGs.

scholarly journals The Mechanisms of CHD8 in Neurodevelopment and Autism Spectrum Disorders

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1133
Author(s):  
Orly Weissberg ◽  
Evan Elliott
Keyword(s):  
Neuronal Development ◽  
Mutant Mouse ◽  
Current Knowledge ◽  
Transcriptional Regulator ◽  
Cell Types ◽  
Dna Binding Protein ◽  
Autism Spectrum ◽  
Cellular Processes ◽  
Spectrum Disorders

Chromodomain-helicase-DNA-binding protein 8 (CHD8) has been identified as one of the genes with the strongest association with autism. The CHD8 protein is a transcriptional regulator that is expressed in nearly all cell types and has been implicated in multiple cellular processes, including cell cycle, cell adhesion, neuronal development, myelination, and synaptogenesis. Considering the central role of CHD8 in the genetics of autism, a deeper understanding of the physiological functions of CHD8 is important to understand the development of the autism phenotype and potential therapeutic targets. Different CHD8 mutant mouse models were developed to determine autism-like phenotypes and to fully understand their mechanisms. Here, we review the current knowledge on CHD8, with an emphasis on mechanistic lessons gained from animal models that have been studied.

scholarly journals Role of an adaptor protein Lin-7B in brain development: possible involvement in autism spectrum disorders

2014 ◽  
Vol 132 (1) ◽  
pp. 61-69 ◽  
Author(s):  
Makoto Mizuno ◽  
Ayumi Matsumoto ◽  
Nanako Hamada ◽  
Hidenori Ito ◽  
Akihiko Miyauchi ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Brain Development ◽  
Adaptor Protein ◽  
Autism Spectrum ◽  
Spectrum Disorders

Examining the Role of Language in Play Among Children With and Without Developmental Disabilities

2020 ◽  
Vol 51 (3) ◽  
pp. 795-806 ◽  
Author(s):  
Elizabeth J. Short ◽  
Rachael Cooper Schindler ◽  
Rita Obeid ◽  
Maia M. Noeder ◽  
Laura E. Hlavaty ◽  
...  
Keyword(s):  
Developmental Disabilities ◽  
Autism Spectrum ◽  
Free Play ◽  
Group Differences ◽  
Typically Developing ◽  
Play Skills ◽  
Critical Aspect ◽  
Hyperactivity Disorder ◽  
Better Than

Purpose Play is a critical aspect of children's development, and researchers have long argued that symbolic deficits in play may be diagnostic of developmental disabilities. This study examined whether deficits in play emerge as a function of developmental disabilities and whether our perceptions of play are colored by differences in language and behavioral presentations. Method Ninety-three children participated in this study (typically developing [TD]; n = 23, developmental language disorders [DLD]; n = 24, attention-deficit/hyperactivity disorder [ADHD]; n = 26, and autism spectrum disorder [ASD]; n = 20). Children were videotaped engaging in free-play. Children's symbolic play (imagination, organization, elaboration, and comfort) was scored under conditions of both audible language and no audible language to assess diagnostic group differences in play and whether audible language impacted raters' perception of play. Results Significant differences in play were evident across diagnostic groups. The presence of language did not alter play ratings for the TD group, but differences were found among the other diagnostic groups. When language was audible, children with DLD and ASD (but not ADHD) were scored poorly on play compared to their TD peers. When language was not audible, children with DLD were perceived to play better than when language was audible. Conversely, children with ADHD showed organizational deficits when language was not available to support their play. Finally, children with ASD demonstrated poor play performance regardless of whether language was audible or not. Conclusions Language affects our understanding of play skills in some young children. Parents, researchers, and clinicians must be careful not to underestimate or overestimate play based on language presentation. Differential skills in language have the potential to unduly influence our perceptions of play for children with developmental disabilities.

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