Identification of the 37-kDa antigen in IDDM as a tyrosine phosphatase-like protein (phogrin) related to IA-2.
Antibodies to islet cell proteins detected as 37,000 and 40,000 M(r), tryptic fragments (37- and 40-kDa antigens) are strongly associated with progression to IDDM. The 40-kDa antigen has recently been identified as the tyrosine phosphatase-like protein IA-2 (ICA512) whereas the 37-kDa antigen has been suggested to be a different protein that has structural similarity to IA-2. A protein, phogrin, that has 80% amino acid sequence identity to IA-2 in the cytoplasmic domain, has recently been cloned from an insulinoma cell cDNA library. In this study, we have investigated possible relationships between the 37-kDa antigen and phogrin. Antibodies to phogrin were detected in sera from patients with IDDM, and these antibodies were strongly correlated with the presence of antibodies to the 37-kDa antigen. Trypsin treatment of immunoprecipitated phogrin generated a 37,000 M(r) fragment. Recombinant phogrin was able to block autoantibody binding to the 37-kDa antigen but not to the 40-kDa antigen, and rabbit antibodies raised to different regions of phogrin depleted insulinoma cell extracts specifically of the 37-kDa antigen. These results demonstrate that the 37-kDa antigen in IDDM is indistinguishable from phogrin and show that two distinct tyrosine phosphatase-related proteins are major targets of the autoimmune response in the disease.
Hawkes
C J
CJ
Department of Medicine, King's College School of Medicine and Dentistry, London, UK.
Wasmeier
C
C
Christie
M R
MR
Hutton
J C
JC
D000818:Animals; D000906:Antibodies; D000937:Antigen-Antibody Reactions; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000276:immunology*; D003001:Cloning, Molecular; D003429:Cross Reactions; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D007340:Insulinoma; D007515:Islets of Langerhans / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D008970:Molecular Weight; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000276:immunology*; D009679:Nuclear Family; D010190:Pancreatic Neoplasms; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000276:immunology*; D011817:Rabbits; D051381:Rats; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000276:immunology; D012016:Reference Values
D000906:Antibodies; D001323:Autoantibodies; D001324:Autoantigens; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; C024211:islet cell antibody; C516862:PTPRN protein, human; C102889:PTPRN2 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516864:Ptprn protein, rat; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8