Suppressor of cytokine signaling 3 controls lysosomal routing of G-CSF receptor.
The hematopoietic system provides an attractive model for studying growth factor-controlled expansion and differentiation of cells in relation to receptor routing and its consequences for signal transduction. Suppressor of cytokine signaling (SOCS) proteins regulate receptor signaling partly via their ubiquitin ligase (E3)-recruiting SOCS box domain. Whether SOCS proteins affect signaling through modulating intracellular trafficking of receptors is unknown. Here, we show that a juxtamembrane lysine residue (K632) of the granulocyte colony-stimulating factor receptor (G-CSFR) plays a key role in receptor routing and demonstrate that the effects of SOCS3 on G-CSF signaling to a major extent depend on this lysine. Mutation of K632 causes accumulation of G-CSFR in early endosomes and leads to sustained activation of signal transducer and activator of transcription 5 and ERK, but not protein kinase B. Myeloid progenitors expressing G-CSFR mutants lacking K632 show a perturbed proliferation/differentiation balance in response to G-CSF. This is the first demonstration of SOCS-mediated ubiquitination and routing of a cytokine receptor and its impact on maintaining an appropriate signaling output.
Irandoust
Mahban I
MI
Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
Aarts
Lambertus H J
LH
Roovers
Onno
O
Gits
Judith
J
Erkeland
Stefan J
SJ
Touw
Ivo P
IP
D020816:Amino Acid Motifs; D000818:Animals; D049109:Cell Proliferation; D004705:Endocytosis; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008239:Lysine / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D021381:Protein Transport; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D008024:Ligands; D050505:Mutant Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; C106644:SOCS3 protein, human; D050799:STAT5 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D025801:Ubiquitin; D008239:Lysine