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) t ryptic fragments (37- and 40-kDa antigens) are strongly associated wit h 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 str uctural similarity to IA-2. A protein, phogrin, that has 80% amino aci d sequence identity to IA-2 in the cytoplasmic domain, has recently be en cloned hom an insulinoma cell cDNA library. in this study, we have investigated possible relationships between the 37-kDa antigen and pho grin. Antibodies to phogrin were detected in sera from patients with I DDM, and these antibodies were strongly correlated with the presence o f antibodies to the 37-kDa antigen. Trypsin treatment of immunoprecipi tated phogrin generated a 37,000 M(r) fragment. Recombinant phogrin wa s 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-kD a antigen. These results demonstrate that the 37-kDa antigen in IDDM i s indistinguishable from phogrin and show that two distinct tyrosine p hosphatase-related proteins are major targets of the autoimmune respon se in the disease.