Showing papers by "Urban Lendahl published in 2005"
TL;DR: Molecular insights into how reduced oxygen levels control the cellular differentiation status are provided and a role for Notch is demonstrated in this process.
1,090 citations
TL;DR: Glycosylation acceptor sequences were introduced into full-length human PS1, and the results showed that the first hydrophilic loop is oriented toward the lumen of the endoplasmic reticulum, whereas the N terminus and large hydrophobic loop are in the cytosol.
211 citations
TL;DR: It is suggested that overexpressed galanin in some tissues of these mice can be released and via a receptor-mediated action influence pathophysiological processes.
55 citations
TL;DR: The generation of a mouse knockin model for one of the most prevalent CADASIL mutations, an arginine to cysteine transition at position 141, R141C, which corresponds to mutation R142C in mouse NOTCH 3, is described.
Abstract: CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, MIM 125310) is a genetic vascular dementia disease that is linked to missense mutations, small in-frame deletions, and splice site mutations in the human Notch 3 gene. Here we describe the generation of a mouse knockin model for one of the most prevalent CADASIL mutations, an arginine to cysteine transition at position 141, R141C, which corresponds to mutation R142C in mouse NOTCH 3. CADASIL(R142C) mice show no apparent CADASIL-like phenotype after histological and MRI analysis. The NOTCH 3 (R142C) receptor is processed normally and does not appear to accumulate the ectodomain, which has been observed in CADASIL patients. We discuss possible reasons for the different outcomes of the same germline CADASIL mutation in mice and humans.
41 citations
TL;DR: It is demonstrated that Aph‐1 is present at the cell surface, presumably in active γ‐secretase complexes, and interacts with the Notch receptor, both before and after ligand activation.
Abstract: The activity of the γ-secretase complex is critical for the processing of a number of transmembrane proteins, including Notch. Functional γ-secretase activity can be reconstituted from four proteins – presenilin, nicastrin, Pen-2 and Aph-1 – but the role of the individual proteins remains unclear. In this report we describe the cellular localization and protein interactions of Aph-1, with particular regard to Notch receptor processing. We found that Aph-1 is present at the cell surface, where it interacts with Pen-2, the mature forms of presenilin and nicastrin, and full-length Notch. Aph-1 also interacts with a truncated form of Notch, which is a direct substrate for γ-secretase, but not with the Notch intracellular domain. Immunoprecipitation data for Notch and Aph-1 showed that the Notch-containing γ-secretase complexes most likely form a small subset of the total number of γ-secretase complexes. In conclusion, these data demonstrate that Aph-1 is present at the cell surface, presumably in active γ-secretase complexes, and interacts with the Notch receptor, both before and after ligand activation.
28 citations
TL;DR: Functional similarity data show that endoproteolysis, NTF–CTF interactions, and the assembly and activity of γ‐secretase complexes are very conserved between PS1 and PS2.
Abstract: The gamma-secretase complex processes substrate proteins within membranes and consists of four proteins: presenilin (PS), nicastrin, Aph-1 and Pen-2. PS harbours the enzymatic activity of the complex, and there are two mammalian PS homologues: PS1 and PS2. PS undergoes endoproteolysis, generating the N- and C-terminal fragments, NTF and CTF, which represent the active species of PS. To characterize the functional similarity between complexes of various PS composition, we analysed PS1, PS2, and chimeric PS composed of the NTF from PS1 and CTF from PS2, or vice versa, in assembly and function of the gamma-secretase complex. Chimeric PSs, like PS1 and PS2, undergo normal endoproteolysis when introduced into cells devoid of endogenous PS. Furthermore, PS2 CTF can, at least partially, restore processing in a truncated PS1, which cannot undergo endoproteolysis. All PS forms enable maturation of nicastrin and cleave full length Notch receptors, indicating that both PS1 and PS2 are present at the cell surface. Finally, when co-introduced as separate molecules, NTF and CTF of different PS origin reconstitute gamma-secretase activity. In conclusion, these data show that endoproteolysis, NTF-CTF interactions, and the assembly and activity of gamma-secretase complexes are very conserved between PS1 and PS2.
21 citations