scholarly journals The Endocytic Adaptor Protein ARH Associates with Motor and Centrosomal Proteins and Is Involved in Centrosome Assembly and Cytokinesis

2008 ◽  
Vol 19 (7) ◽  
pp. 2949-2961 ◽  
Author(s):  
Sanna Lehtonen ◽  
Mehul Shah ◽  
Rikke Nielsen ◽  
Noriaki Iino ◽  
Jennifer J. Ryan ◽  
...  
Keyword(s):  
Ldl Receptor ◽  
Adaptor Protein ◽  
Membrane Vesicles ◽  
Cell Types ◽  
Embryonic Fibroblasts ◽  
Spindle Poles ◽  
Autosomal Recessive Hypercholesterolemia ◽  
Intermediate Chains ◽  
Centrosomal Proteins ◽  
Isolated Membrane Vesicles

Numerous proteins involved in endocytosis at the plasma membrane have been shown to be present at novel intracellular locations and to have previously unrecognized functions. ARH (autosomal recessive hypercholesterolemia) is an endocytic clathrin-associated adaptor protein that sorts members of the LDL receptor superfamily (LDLR, megalin, LRP). We report here that ARH also associates with centrosomes in several cell types. ARH interacts with centrosomal (γ-tubulin and GPC2 and GPC3) and motor (dynein heavy and intermediate chains) proteins. ARH cofractionates with γ-tubulin on isolated centrosomes, and γ-tubulin and ARH interact on isolated membrane vesicles. During mitosis, ARH sequentially localizes to the nuclear membrane, kinetochores, spindle poles and the midbody. Arh−/− embryonic fibroblasts (MEFs) show smaller or absent centrosomes suggesting ARH plays a role in centrosome assembly. Rat-1 fibroblasts depleted of ARH by siRNA and Arh−/− MEFs exhibit a slower rate of growth and prolonged cytokinesis. Taken together the data suggest that the defects in centrosome assembly in ARH depleted cells may give rise to cell cycle and mitotic/cytokinesis defects. We propose that ARH participates in centrosomal and mitotic dynamics by interacting with centrosomal proteins. Whether the centrosomal and mitotic functions of ARH are related to its endocytic role remains to be established.

Abstract 1921: Clinical Impact of Heterozygous Carrier of Autosomal Recessive Hypercholesterolemia on Asymptomatic Hyperlipidemic Patients: Evidence From Familial Gene Analysis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hayato Tada ◽  
Masa-aki Kawashiri ◽  
Tohru Noguchi ◽  
Chiaki Nakanishi ◽  
Masayuki Tsuchida ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Genetic Defect ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Serum Triglyceride ◽  
Adaptor Protein ◽  
Receptor Internalization ◽  
Single Mutation ◽  
Heterozygous Carrier ◽  
Autosomal Recessive Hypercholesterolemia

Autosomal recessive hypercholesterolemia (ARH) is an extremely rare genetic defect, and is recognized only around 50 cases in all over the world. The genetic cause of ARH is mutation in an adaptor protein involved in low-density lipoprotein (LDL) receptor internalization, which results in marked elevation of serum LDL cholesterol (LDL-C) and premature atherosclerosis. Therefore, few data exist regarding the clinical significance about the heterozygous carrier of ARH. We recently identified the second ARH patient (Ins C 599 ) in Japan and his some relatives who have the same single mutation (heterozygous). We identified 11 heterozygous ARH carriers (male=5, mean age=48.2) and 7 non-carriers (male=3, mean age=53.3) in the same family. In addition, we screened the same mutations in unrelated consecutive 500 hyperlipidemic patients (male=32, mean age=49.4) with mean LDL-C of 225.2±6.1mg/dl using PCR to determine its frequency and examined their clinical features. We identified an unrelated heterozygous ARH carrier and a non-carrier in the same family among unrelated to the original family. Serum LDL-C levels of heterozygous ARH carriers (mean=153.8±35.8mg/dl) were significantly higher than those of non-carriers (mean=108.2±41.4mg/dl, p<0.05). Serum triglyceride (151.9±110.7mg/dl vs 140.4±48.8mg/dl) and high-density lipoprotein cholesterol (57.4±11.0mg/dl vs 54.0±11.9mg/dl) levels were not different between them. Interestingly, heterozygous ARH carriers didn’t show any xanthomas including Achilles tendon (6.4±1.1mm vs 5.7±1.1mm) in contrast to FH, which is frequently associated with typical xanthoma. These results demonstrate that heterozygous ARH (Ins C 599 ) carriers show higher LDL-C levels compared with non-carrier family member without tendon xanthomas observed in FH. We suggest that heterozygous ARH (Ins C 599 ) carrier may explain a part of primary hypercholesterolemia.

Focusing on spindle poles

1998 ◽  
Vol 111 (11) ◽  
pp. 1477-1481 ◽  
Author(s):  
D.A. Compton
Keyword(s):  
Light Microscopy ◽  
Dominant Role ◽  
Cell Types ◽  
Common Mechanism ◽  
Microtubule Nucleation ◽  
Specialized Cell ◽  
Spindle Poles ◽  
Meiotic Spindles ◽  
Centrosomal Proteins

Spindle poles are discernible by light microscopy as the sites where microtubules converge at the ends of both mitotic and meiotic spindles. In most cell types centrosomes are present at spindle poles due to their dominant role in microtubule nucleation. However, in some specialized cell types microtubules converge into spindle poles in the absence of centrosomes. Thus, spindle poles in centrosomal and acentrosomal cell types are structurally different, and it is this structural dichotomy that has created confusion as to the mechanism by which microtubules are organized into spindle poles. This review summarizes a series of recent articles that begin to resolve this confusion by demonstrating that spindle poles are organized through a common mechanism by a conserved group of non-centrosomal proteins in the presence or absence of centrosomes.

Rotavirus interaction with isolated membrane vesicles.

1994 ◽  
Vol 68 (6) ◽  
pp. 4009-4016 ◽  
Author(s):  
M C Ruiz ◽  
S R Alonso-Torre ◽  
A Charpilienne ◽  
M Vasseur ◽  
F Michelangeli ◽  
...  
Keyword(s):  
Membrane Vesicles ◽  
Isolated Membrane Vesicles

scholarly journals Lis1 is essential for cortical microtubule organization and desmosome stability in the epidermis

2011 ◽  
Vol 194 (4) ◽  
pp. 631-642 ◽  
Author(s):  
Kaelyn D. Sumigray ◽  
Hsin Chen ◽  
Terry Lechler
Keyword(s):  
Cortical Microtubule ◽  
Cell Types ◽  
Epidermal Differentiation ◽  
Cell Cortex ◽  
Microtubule Organization ◽  
Specific Subset ◽  
Keratin Filaments ◽  
Perinatal Lethality ◽  
Cytoskeletal Networks ◽  
Centrosomal Proteins

Desmosomes are cell–cell adhesion structures that integrate cytoskeletal networks. In addition to binding intermediate filaments, the desmosomal protein desmoplakin (DP) regulates microtubule reorganization in the epidermis. In this paper, we identify a specific subset of centrosomal proteins that are recruited to the cell cortex by DP upon epidermal differentiation. These include Lis1 and Ndel1, which are centrosomal proteins that regulate microtubule organization and anchoring in other cell types. This recruitment was mediated by a region of DP specific to a single isoform, DPI. Furthermore, we demonstrate that the epidermal-specific loss of Lis1 results in dramatic defects in microtubule reorganization. Lis1 ablation also causes desmosomal defects, characterized by decreased levels of desmosomal components, decreased attachment of keratin filaments, and increased turnover of desmosomal proteins at the cell cortex. This contributes to loss of epidermal barrier activity, resulting in completely penetrant perinatal lethality. This work reveals essential desmosome-associated components that control cortical microtubule organization and unexpected roles for centrosomal proteins in epidermal function.

A combined LDL receptor/LDL receptor adaptor protein 1 mutation as the cause for severe familial hypercholesterolemia

Gene ◽  
2013 ◽  
Vol 521 (1) ◽  
pp. 200-203 ◽  
Author(s):  
Muhidien Soufi ◽  
Stephan Rust ◽  
Michael Walter ◽  
Juergen R. Schaefer
Keyword(s):  
Familial Hypercholesterolemia ◽  
Ldl Receptor ◽  
Adaptor Protein

scholarly journals Differential Requirement for TANK-binding Kinase-1 in Type I Interferon Responses to Toll-like Receptor Activation and Viral Infection

2004 ◽  
Vol 199 (12) ◽  
pp. 1651-1658 ◽  
Author(s):  
Andrea K. Perry ◽  
Edward K. Chow ◽  
Julia B. Goodnough ◽  
Wen-Chen Yeh ◽  
Genhong Cheng
Keyword(s):  
Viral Infection ◽  
Nuclear Translocation ◽  
Sendai Virus ◽  
Cell Types ◽  
Receptor Activation ◽  
Northern Blotting ◽  
Type I ◽  
Toll Like Receptor ◽  
Embryonic Fibroblasts ◽  
Iκb Kinase

TANK-binding kinase-1 (TBK1) and the inducible IκB kinase (IKK-i) have been shown recently to activate interferon (IFN) regulatory factor-3 (IRF3), the primary transcription factor regulating induction of type I IFNs. Here, we have compared the role and specificity of TBK1 in the type I IFN response to lipopolysaccharide (LPS), polyI:C, and viral challenge by examining IRF3 nuclear translocation, signal transducer and activator of transcription 1 phosphorylation, and induction of IFN-regulated genes. The LPS and polyI:C-induced IFN responses were abolished and delayed, respectively, in macrophages from mice with a targeted disruption of the TBK1 gene. When challenged with Sendai virus, the IFN response was normal in TBK1−/− macrophages, but defective in TBK1−/− embryonic fibroblasts. Although both TBK1 and IKK-i are expressed in macrophages, only TBK1 but not IKK-i was detected in embryonic fibroblasts by Northern blotting analysis. Furthermore, the IFN response in TBK1−/− embryonic fibroblasts can be restored by reconstitution with wild-type IKK-i but not a mutant IKK-i lacking kinase activity. Thus, our studies suggest that TBK1 plays an important role in the Toll-like receptor–mediated IFN response and is redundant with IKK-i in the response of certain cell types to viral infection.

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