I-SMAD recruits type I receptor phosphatase and ubiquitin ligases to mediate receptor downregulation

2006 ◽  
Vol 17 ◽  
Author(s):  
CH Heldin ◽  
A Moustakas ◽  
L Huminiecki ◽  
B Jassal
Keyword(s):  
Ubiquitin Ligases ◽  
Type I ◽  
Receptor Downregulation ◽  
Receptor Phosphatase

scholarly journals NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-β (transforming growth factor-β) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-β type I receptor

2005 ◽  
Vol 386 (3) ◽  
pp. 461-470 ◽  
Author(s):  
Go KURATOMI ◽  
Akiyoshi KOMURO ◽  
Kouichiro GOTO ◽  
Masahiko SHINOZAKI ◽  
Keiji MIYAZAWA ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Ubiquitin Ligases ◽  
Transforming Growth Factor Β ◽  
Precursor Cell ◽  
Neural Precursor ◽  
Type I ◽  
Dependent Manner ◽  
E3 Ubiquitin Ligases ◽  
Neural Precursor Cell

Inhibitory Smad, Smad7, is a potent inhibitor of TGF-β (transforming growth factor-β) superfamily signalling. By binding to activated type I receptors, it prevents the activation of R-Smads (receptor-regulated Smads). To identify new components of the Smad pathway, we performed yeast two-hybrid screening using Smad7 as bait, and identified NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) as a direct binding partner of Smad7. NEDD4-2 is structurally similar to Smurfs (Smad ubiquitin regulatory factors) 1 and 2, which were identified previously as E3 ubiquitin ligases for R-Smads and TGF-β superfamily receptors. NEDD4-2 functions like Smurfs 1 and 2 in that it associates with TGF-β type I receptor via Smad7, and induces its ubiquitin-dependent degradation. Moreover, NEDD4-2 bound to TGF-β-specific R-Smads, Smads 2 and 3, in a ligand-dependent manner, and induced degradation of Smad2, but not Smad3. However, in contrast with Smurf2, NEDD4-2 failed to induce ubiquitination of SnoN (Ski-related novel protein N), although NEDD4-2 bound to SnoN via Smad2 more strongly than Smurf2. We showed further that overexpressed NEDD4-2 prevents transcriptional activity induced by TGF-β and BMP, whereas silencing of the NEDD4-2 gene by siRNA (small interfering RNA) resulted in enhancement of the responsiveness to TGF-β superfamily cytokines. These data suggest that NEDD4-2 is a member of the Smurf-like C2-WW-HECT (WW is Trp-Trp and HECT is homologous to the E6-accessory protein) type E3 ubiquitin ligases, which negatively regulate TGF-β superfamily signalling through similar, but not identical, mechanisms to those used by Smurfs.

scholarly journals E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression

2021 ◽  
Vol 22 (2) ◽  
pp. 476
Author(s):  
Abhishek Sinha ◽  
Prasanna Vasudevan Iyengar ◽  
Peter ten Dijke
Keyword(s):  
Signaling Pathway ◽  
Cancer Progression ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Ubiquitin Ligases ◽  
Specific Cell ◽  
Type I ◽  
E3 Ubiquitin Ligases ◽  
Tgfβ Signaling ◽  
E3 Ligases

Transforming growth factor β (TGFβ) is a secreted growth and differentiation factor that influences vital cellular processes like proliferation, adhesion, motility, and apoptosis. Regulation of the TGFβ signaling pathway is of key importance to maintain tissue homeostasis. Perturbation of this signaling pathway has been implicated in a plethora of diseases, including cancer. The effect of TGFβ is dependent on cellular context, and TGFβ can perform both anti- and pro-oncogenic roles. TGFβ acts by binding to specific cell surface TGFβ type I and type II transmembrane receptors that are endowed with serine/threonine kinase activity. Upon ligand-induced receptor phosphorylation, SMAD proteins and other intracellular effectors become activated and mediate biological responses. The levels, localization, and function of TGFβ signaling mediators, regulators, and effectors are highly dynamic and regulated by a myriad of post-translational modifications. One such crucial modification is ubiquitination. The ubiquitin modification is also a mechanism by which crosstalk with other signaling pathways is achieved. Crucial effector components of the ubiquitination cascade include the very diverse family of E3 ubiquitin ligases. This review summarizes the diverse roles of E3 ligases that act on TGFβ receptor and intracellular signaling components. E3 ligases regulate TGFβ signaling both positively and negatively by regulating degradation of receptors and various signaling intermediates. We also highlight the function of E3 ligases in connection with TGFβ’s dual role during tumorigenesis. We conclude with a perspective on the emerging possibility of defining E3 ligases as drug targets and how they may be used to selectively target TGFβ-induced pro-oncogenic responses.

Heat-Etching with a Bullivant Type II Simple Freeze-Cleave Device

1970 ◽  
Vol 28 ◽  
pp. 106-107 ◽  
Author(s):  
Ronald S. Weinstein ◽  
N. Scott McNutt
Keyword(s):  
New Zealand ◽  
General Hospital ◽  
Massachusetts General Hospital ◽  
Type I ◽  
Type Ii ◽  
Collaborative Effort ◽  
Temperature And Pressure ◽  
The University

The Type I simple cold block device was described by Bullivant and Ames in 1966 and represented the product of the first successful effort to simplify the equipment required to do sophisticated freeze-cleave techniques. Bullivant, Weinstein and Someda described the Type II device which is a modification of the Type I device and was developed as a collaborative effort at the Massachusetts General Hospital and the University of Auckland, New Zealand. The modifications reduced specimen contamination and provided controlled specimen warming for heat-etching of fracture faces. We have now tested the Mass. General Hospital version of the Type II device (called the “Type II-MGH device”) on a wide variety of biological specimens and have established temperature and pressure curves for routine heat-etching with the device.

Two Distinct Types of Microfilaments in the Cytoplasm of Human Adenohypophysial Cells

1973 ◽  
Vol 31 ◽  
pp. 668-669
Author(s):  
E. Horvath ◽  
K. Kovacs ◽  
I. E. Stratmann ◽  
C. Ezrin
Keyword(s):  
Pituitary Tumors ◽  
Average Diameter ◽  
Anterior Lobe ◽  
Uranyl Acetate ◽  
Type I ◽  
Breast Cancer Patients ◽  
Human Pituitary ◽  
Severe Diabetes ◽  
Pituitary Glands ◽  
Membrane Bound

Surgically removed human pituitary glands as well as pituitary tumors fixed in glutaraldehyde, postfixed in osmium tetroxide, embedded in epon resin, stained with uranyl acetate and lead citrate have been investigated by electron microscopy in order to correlate ultrastructure with functional activity. In the course of this study two distinct types of microfilaments have been identified in the cytoplasm of adenohypophysiocytes.Type I microfilaments (Fig. 1) were found in the cytoplasm of anterior lobe cells of five female subjects with disseminated mammary cancer and two patients with severe diabetes mellitus. The breast cancer patients were treated pre-operatively for various periods of time with different doses of oxysteroids. The microfilaments had an average diameter of JO A, formed parallel bundles, were scattered irregularly in the cytoplasm and were frequently located in the perikaryon. They were not membrane-bound and failed to show any periodicity.

The diagnosis of metabolic storage disease in skin biopsies (a light-, electronmicroscopic, and analytical study)

1978 ◽  
Vol 36 (2) ◽  
pp. 648-649
Author(s):  
W. Jurecka ◽  
W. Gebhart ◽  
H. Lassmann
Keyword(s):  
Storage Disease ◽  
Hunter Syndrome ◽  
Histochemical Demonstration ◽  
Sweat Glands ◽  
Type I ◽  
Storage Material ◽  
Scheie Syndrome ◽  
Storage Products ◽  
Skin Biopsies ◽  
Type V

Diagnosis of metabolic storage disease can be established by the determination of enzymes or storage material in blood, urine, or several tissues or by clinical parameters. Identification of the accumulated storage products is possible by biochemical analysis of isolated material, by histochemical demonstration in sections, or by ultrastructural demonstration of typical inclusion bodies. In order to determine the significance of such inclusions in human skin biopsies several types of metabolic storage disease were investigated. The following results were obtained.In MPS type I (Pfaundler-Hurler-Syndrome), type II (Hunter-Syndrome), and type V (Ullrich-Scheie-Syndrome) mainly “empty” vacuoles were found in skin fibroblasts, in Schwann cells, keratinocytes and macrophages (Dorfmann and Matalon 1972). In addition, prominent vacuolisation was found in eccrine sweat glands. The storage material could be preserved in part by fixation with cetylpyridiniumchloride and was also present within fibroblasts grown in tissue culture.

Methionine-Specific Staining of Collagen

1982 ◽  
Vol 40 ◽  
pp. 294-295
Author(s):  
E.M. Kuhn ◽  
K.D. Marenus ◽  
M. Beer
Keyword(s):  
Amino Acids ◽  
Collagen Fibers ◽  
Type Iii Collagen ◽  
Type I ◽  
Electron Microscopic ◽  
Good Correspondence ◽  
Specific Staining ◽  
Type Iii ◽  
Different Types ◽  
Sulfur Containing

Fibers composed of different types of collagen cannot be differentiated by conventional electron microscopic stains. We are developing staining procedures aimed at identifying collagen fibers of different types.Pt(Gly-L-Met)Cl binds specifically to sulfur-containing amino acids. Different collagens have methionine (met) residues at somewhat different positions. A good correspondence has been reported between known met positions and Pt(GLM) bands in rat Type I SLS (collagen aggregates in which molecules lie adjacent to each other in exact register). We have confirmed this relationship in Type III collagen SLS (Fig. 1).

Labelling of non-A, non-B hepatitis infected chimpanzee hepatocytes with nuclease-gold conjugates

1984 ◽  
Vol 42 ◽  
pp. 250-251
Author(s):  
G. D. Gagne ◽  
M. F. Miller ◽  
D. A. Peterson
Keyword(s):  
Endoplasmic Reticulum ◽  
Experimental Infection ◽  
Uranyl Acetate ◽  
Type I ◽  
Cellular Injury ◽  
Type Ii ◽  
Tubular Structures ◽  
Type Iii ◽  
Type Iv ◽  
Infected Chimpanzee

Experimental infection of chimpanzees with non-A, non-B hepatitis (NANB) or with delta agent hepatitis results in the appearance of characteristic cytoplasmic alterations in the hepatocytes. These alterations include spongelike inclusions (Type I), attached convoluted membranes (Type II), tubular structures (Type III), and microtubular aggregates (Type IV) (Fig. 1). Type I, II and III structures are, by association, believed to be derived from endoplasmic reticulum and may be morphogenetically related. Type IV structures are generally observed free in the cytoplasm but sometimes in the vicinity of type III structures. It is not known whether these structures are somehow involved in the replication and/or assembly of the putative NANB virus or whether they are simply nonspecific responses to cellular injury. When treated with uranyl acetate, type I, II and III structures stain intensely as if they might contain nucleic acids. If these structures do correspond to intermediates in the replication of a virus, one might expect them to contain DNA or RNA and the present study was undertaken to explore this possibility.

Collagen fibrillogenesis in vitro: interaction of types I and V collagen

1986 ◽  
Vol 44 ◽  
pp. 210-211
Author(s):  
Arthur J. Wasserman ◽  
Kathy C. Kloos ◽  
David E. Birk
Keyword(s):  
Type I Collagen ◽  
Corneal Stroma ◽  
Minor Component ◽  
Homogeneous Distribution ◽  
Type I ◽  
Type V Collagen ◽  
Fibril Morphology ◽  
Type V ◽  
In Vitro Interaction

Type I collagen is the predominant collagen in the cornea with type V collagen being a quantitatively minor component. However, the content of type V collagen (10-20%) in the cornea is high when compared to other tissues containing predominantly type I collagen. The corneal stroma has a homogeneous distribution of these two collagens, however, immunochemical localization of type V collagen requires the disruption of type I collagen structure. This indicates that these collagens may be arranged as heterpolymeric fibrils. This arrangement may be responsible for the control of fibril diameter necessary for corneal transparency. The purpose of this work is to study the in vitro assembly of collagen type V and to determine whether the interactions of these collagens influence fibril morphology.

Electron microscopy of keratinocytes cultured on a collagen substrate used as an allograft for the treatment of chronic wounds

1992 ◽  
Vol 50 (2) ◽  
pp. 1104-1105
Author(s):  
Debby A. Jennings ◽  
Michael J. Morykwas ◽  
Louis C. Argenta
Keyword(s):  
Electron Microscopy ◽  
Cell Suspension ◽  
Single Cell ◽  
Chronic Wounds ◽  
Mechanical Stability ◽  
Uv Light ◽  
Type I ◽  
Single Cell Suspension ◽  
Collagen Substrate ◽  
Dermal Collagen

Grafts of cultured allogenic or autogenic keratlnocytes have proven to be an effective treatment of chronic wounds and burns. This study utilized a collagen substrate for keratinocyte and fibroblast attachment. The substrate provided mechanical stability and augmented graft manipulation onto the wound bed. Graft integrity was confirmed by light and transmission electron microscopy.Bovine Type I dermal collagen sheets (100 μm thick) were crosslinked with 254 nm UV light (13.5 Joules/cm2) to improve mechanical properties and reduce degradation. A single cell suspension of third passage neonatal foreskin fibroblasts were plated onto the collagen. Five days later, a single cell suspension of first passage neonatal foreskin keratinocytes were plated on the opposite side of the collagen. The grafts were cultured for one month.The grafts were fixed in phosphate buffered 4% formaldehyde/1% glutaraldehyde for 24 hours. Graft pieces were then washed in 0.13 M phosphate buffer, post-fixed in 1% osmium tetroxide, dehydrated, and embedded in Polybed 812.

Comparative surface and ultrastructural views of methylotrophic bacteria by TEM, STEM, SE, and freeze-etch electron microscopy.

1987 ◽  
Vol 45 ◽  
pp. 792-793
Author(s):  
T.A. Fassel ◽  
M.J. Schaller ◽  
M.E. Lidstrom ◽  
C.C. Remsen
Keyword(s):  
Cytoplasmic Membrane ◽  
Structural Features ◽  
Methylotrophic Bacteria ◽  
Type I ◽  
Type Ii ◽  
Membrane Complex ◽  
Oxidation Of Methane ◽  
Methane Oxidizing Bacteria ◽  
Wall Structures ◽  
Methylomonas Albus

Methylotrophic bacteria play an Important role in the environment in the oxidation of methane and methanol. Extensive intracytoplasmic membranes (ICM) have been associated with the oxidation processes in methylotrophs and chemolithotrophic bacteria. Classification on the basis of ICM arrangement distinguishes 2 types of methylotrophs. Bundles or vesicular stacks of ICM located away from the cytoplasmic membrane and extending into the cytoplasm are present in Type I methylotrophs. In Type II methylotrophs, the ICM form pairs of peripheral membranes located parallel to the cytoplasmic membrane. Complex cell wall structures of tightly packed cup-shaped subunits have been described in strains of marine and freshwater phototrophic sulfur bacteria and several strains of methane oxidizing bacteria. We examined the ultrastructure of the methylotrophs with particular view of the ICM and surface structural features, between representatives of the Type I Methylomonas albus (BG8), and Type II Methylosinus trichosporium (OB-36).

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