title: Scratching the surface: signaling and routing dynamics of the CSF3 receptor.
abstract: Following activation by their cognate ligands, cytokine receptors undergo intracellular routing towards lysosomes where they are degraded. Cytokine receptor signaling does not terminate at the plasma membrane, but continues throughout the endocytotic pathway. The modes of internalization and intracellular trafficking of specific receptors, the level of recycling towards the plasma membrane, the type of protein modifications (phosphorylation, ubiquitination) and the enzymes involved in these processes are remarkably diverse. This heterogeneity may contribute to the fine-tuning of signal amplitudes and duration from different receptors. The colony-stimulating factor 3 receptor (CSF3R) is unique for its balanced signaling output, first leading to proliferation of myeloid progenitors, followed by a cell cycle arrest and granulocytic differentiation. The mechanisms associated with CSF3R signal modulation, involving receptor lysine ubiquitination and redox-controlled phosphatase activities, are to a large extent confined to the signaling endosome. Interactions between signaling endosomes and the endoplasmic reticulum play a key role in this process. Here, we review the mechanisms of intracellular routing of CSF3R, their consequences for myeloid blood cell development and their implications for myeloid diseases.
authors.affiliation: Department of Hematology, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
authors.forename: Karishma
authors.initials: K
authors.lastname: Palande
authors.forename: Annemarie
authors.initials: A
authors.lastname: Meenhuis
authors.forename: Tanja
authors.initials: T
authors.lastname: Jevdjovic
authors.forename: Ivo P
authors.initials: IP
authors.lastname: Touw
mesh_terms: D000818:Animals; D000080984:Congenital Bone Marrow Failure Syndromes; D004705:Endocytosis / Q000235:genetics; D010450:Endopeptidases / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000503:physiopathology; D008239:Lysine / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D009503:Neutropenia / Q000151:congenital / Q000503:physiopathology; D010084:Oxidation-Reduction; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D016184:Receptors, Colony-Stimulating Factor / Q000502:physiology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C517047:CSF3R protein, human; D056827:Endosomal Sorting Complexes Required for Transport; D016184:Receptors, Colony-Stimulating Factor; D053612:Janus Kinases; C516607:PTPN1 protein, human; C509249:PTPN6 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase; D008239:Lysine