Granulocyte macrophage-colony stimulating factor reduces the affinity of SHP-2 for the ITIM of CLECSF6 in neutrophils: a new mechanism of action for SHP-2.
Proteins that bear immunoreceptor tyrosine based inhibitory motifs (ITIM) are believed to participate in the repression of cell activation via phosphatases such as SHP-1, SHP-2 and/or SHIP-1. CLECSF6, also called DCIR, is a transmembrane protein expressed on leukocytes and predominantly on neutrophils that bears one ITIM pattern. This feature confers to CLECSF6 a role in the repression of cell activation. In order to better understand its role in neutrophil signalling, we analysed the binding of phosphatases to the ITIM of CLECSF6. We showed that a peptide bearing the ITIM of CLECSF6 in its phosphorylated form associates with both SHP-1 and SHP-2. Phosphorylated SHP-1 binds the ITIM whereas phosphorylated SHP-2 does not. In addition, granulocyte macrophage-colony stimulating factor (GM-CSF) reduces the binding of SHP-2 to the ITIM of CLECSF6 while enhancing the phosphorylation level of SHP-2. GM-CSF is known to recruit SHP-2 to its receptor. These data suggest that the phosphorylation of SHP-2 by GM-CSF promotes the binding of SHP-2 to the GM-CSF receptor to the disadvantage of CLECSF6. Therefore, upon a treatment with GM-CSF, SHP-2 could move from a CLECSF6 associated signalosome with a repressor function to a GM-CSF receptor associated signalosome with an activator function.
Richard
Manon
M
Laboratoire de Recherche sur l'Arthrite et l'Inflammation, Department of Medicine, Faculty of Medicine, Centre Hospitalier de l'Université Laval, Sainte-Foy, Qué., Canada.
Thibault
Nathalie
N
Veilleux
Patricia
P
Gareau-Pagé
Geneviève
G
Beaulieu
André D
AD
D020816:Amino Acid Motifs; D003902:Detergents / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D037181:Lectins, C-Type / Q000737:chemistry / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
C423004:CLEC4A protein, human; D003902:Detergents; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D010455:Peptides; D011971:Receptors, Immunologic; D014443:Tyrosine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010744:Phosphoric Monoester Hydrolases; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases