ArticleThe Journal of biological chemistry2009
Ligand-independent thrombopoietin mutant receptor requires cell surface localization for endogenous activity.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
8 citing papers in PubMed, 14 citations in OpenAlex.
- Article
- The Thrombopoietin Receptor, MPL, Is a Therapeutic Target of Opportunity in the MPN.Frontiers in oncology · 2021Review
- Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface.Leukemia · 2020Article
- Thrombopoietin is required for full phenotype expression in a JAK2V617F transgenic mouse model of polycythemia vera.PloS one · 2020Article
- His499 Regulates Dimerization and Prevents Oncogenic Activation by Asparagine Mutations of the Human Thrombopoietin Receptor.The Journal of biological chemistry · 2016Article
- Intracellular signaling prevents effective blockade of oncogenic gp130 mutants by neutralizing antibodies.Cell communication and signaling : CCS · 2014Article
- Eliminative signaling by Janus kinases: role in the downregulation of associated receptors.Journal of cellular biochemistry · 2014Review
- Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis.Nature medicine · 2013Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The activating W515L mutation in the thrombopoietin receptor (MPL) has been identified in primary myelofibrosis and essential thrombocythemia. MPL belongs to a subset of the cytokine receptor superfamily that requires the JAK2 kinase for signaling. We examined whether the ligand-independent MPL(W515L) mutant could signal intracellularly. Addition of the endoplasmic reticulum (ER) retention KDEL sequence to the receptor C terminus efficiently locked MPL(W515L) within its natural ER/Golgi maturation pathway. In contrast to cells expressing the parental MPL(W515L), MPL(W515L)-KDEL-expressing FDC-P1 cells were unable to grow autonomously and to produce tumors in nude mice. When observed, tumor nodules resulted from in vivo selection of cells leaking the receptor at their surface. JAK2 co-immunoprecipitated with MPL(W515L)-KDEL but was not phosphorylated. We generated disulfide-bonded MPL(W515L) homodimers by the S402C substitution, both in the normal and KDEL context. Unlike MPL(W515L)-KDEL, MPL(W515L-S402C)-KDEL signaled constitutively and exhibited cell surface localization. These data establish that MPL(W515L) with appended JAK2 matures through the ER/Golgi system in an inactive conformation and suggest that the MPL(W515L)/JAK2 complex requires membrane localization for JAK2 phosphorylation, resulting in autonomous receptor signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.