Reduced Tyk2/SHP-1 interaction and lack of SHP-1 mutation in a kindred of familial hemophagocytic lymphohistiocytosis.
Familial hemophagocytic lymphohistiocytosis (FHLH) is an autosomal recessive disease with features similar to those of the murine motheaten phenotype resulting from mutations of protein tyrosine phosphatase SHP-1. This has raised the possibility that defects in SHP-1 or SHP-1-regulated signaling molecules may be present in FHLH. In this study, we examined SHP-1 protein and transcript in the peripheral blood mononuclear cells (PBMC) of an FHLH family. Our results show that the FHLH patient and the parents express comparable levels of a single SHP-1 protein and that the SHP-1 cDNA clone from the patient contains no mutation in the coding region. Interestingly, a reduced association of SHP-1 with the Jak family kinase Tyk2 was detected in the patient and the defect appears to have been inherited from one of the parents. This reduced SHP-1/Tyk2 association is likely due to a defect in Tyk2 or in cellular factors regulating Tyk2, because we found no abnormalities in SHP-1 or in SHP-1 association with the other Jak kinases. These data demonstrate that the SHP-1 gene is intact in FHLH and that the defect in some cases with this disease may involve signaling molecules regulated by SHP-1.
Tabrizi
M
M
Department of Cancer Biology, The Lerner Research Institute, Cleveland Clinic Foundation, OH 44195, USA.
Yang
W
W
Jiao
H
H
DeVries
E M
EM
Platanias
L C
LC
Arico
M
M
Yi
T
T
D000328:Adult; D000818:Animals; D019556:COS Cells / Q000378:metabolism; D002648:Child; D018076:DNA, Complementary / Q000235:genetics; D015616:Histiocytosis, Non-Langerhans-Cell / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D009154:Mutation; D010375:Pedigree; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D053634:TYK2 Kinase
D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human; 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