ArticleThe Journal of biological chemistry2015
Inside-out Regulation of Ectodomain Cleavage of Cluster-of-Differentiation-44 (CD44) and of Neuregulin-1 Requires Substrate Dimerization.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 46 citations in OpenAlex.
- Protein O-Glycosylation Shapes Lymphatic Endothelia and Lymph Node Macrophage Populations.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Targeting CD44 reverses sphingomyelin-induced oligodendrocyte maturation arrest in acid sphingomyelinase deficiency.EMBO molecular medicine · 2026Article
- The cell adhesion molecule CD44 acts as a modulator of 5-HT7 receptor functions.Cell communication and signaling : CCS · 2024Article
- CD44: A New Prognostic Marker in Colorectal Cancer?Cancers · 2024Review
- CD44 Intracellular Domain: A Long Tale of a Short Tail.Cancers · 2023Review
- Inducing prion protein shedding as a neuroprotective and regenerative approach in pathological conditions of the brain: from theory to facts.Neural regeneration research · 2023Review
- CD44 Contributes to the Regulation of MDR1 Protein and Doxorubicin Chemoresistance in Osteosarcoma.International journal of molecular sciences · 2022Article
- Molecular mechanism of CD44 homodimerization modulated by palmitoylation and membrane environments.Biophysical journal · 2022Article
- Ligands binding to the prion protein induce its proteolytic release with therapeutic potential in neurodegenerative proteinopathies.Science advances · 2021Article
- GPR37 is processed in the N-terminal ectodomain by ADAM10 and furin.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- ADAM10 Site-Dependent Biology: Keeping Control of a Pervasive Protease.International journal of molecular sciences · 2021Review
- ADAM10 is involved in the oncogenic process and chemo-resistance of triple-negative breast cancer via regulating Notch1 signaling pathway, CD44 and PrPc.Cancer cell international · 2021Article
- Proteolytic Processing of CD44 and Its Implications in Cancer.Stem cells international · 2021Review
- A low MW inhibitor of CD44 dimerization for the treatment of glioblastoma.British journal of pharmacology · 2020Article
- Neuregulin 1: an intriguing therapeutic target for neurodevelopmental disorders.Translational psychiatry · 2020Review
- Molecular mechanism for bidirectional regulation of CD44 for lipid raft affiliation by palmitoylations and PIP2.PLoS computational biology · 2020Article
- Article
- L1cam-mediated developmental processes of the nervous system are differentially regulated by proteolytic processing.Scientific reports · 2019Article
- Molecular Dynamics of the Association of L-Selectin and FERM Regulated by PIP2.Biophysical journal · 2018Article
- Gamma secretase dependent release of the CD44 cytoplasmic tail upregulates IFI16 in cd44-/- tumor cells, MEFs and macrophages.PloS one · 2018Article
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
Ectodomain shedding of transmembrane precursor proteins generates numerous life-essential molecules, such as epidermal growth factor receptor ligands. This cleavage not only releases the regulatory growth factor, but it is also the required first step for the subsequent processing by γ-secretase and the release of gene regulatory intracellular fragments. Signaling within the cell modifies the cytoplasmic tails of substrates, a step important in starting the specific and regulated cleavage of a large number of studied substrates. Ectodomain cleavage occurs, however, on the outside of the plasma membrane and is carried out by membrane-bound metalloproteases. How the intracellular domain modification communicates with the ectodomain of the substrate to allow for cleavage to occur is unknown. Here, we show that homodimerization of a cluster-of-differentiation-44 or of pro-neuregulin-1 monomers represents an essential pre-condition for their regulated ectodomain cleavage. Both substrates are associated with their respective metalloproteases under both basal or cleavage-stimulated conditions. These interactions only turn productive by specific intracellular signal-induced intracellular domain modifications of the substrates, which in turn regulate metalloprotease access to the substrates' ectodomain and cleavage. We propose that substrate intracellular domain modification induces a relative rotation or other positional change of the dimerization partners that allow metalloprotease cleavage in the extracellular space. Our findings fill an important gap in understanding substrate-specific inside-out signal transfer along cleaved transmembrane proteins and suggest that substrate dimerization (homo- or possibly heterodimerization) might represent a general principle in ectodomain shedding.
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