PTPN22
PTPN22 encodes LYP, a lymphoid-enriched non-receptor phosphatase combining an N-terminal catalytic domain with an extended C-terminal proline-rich region that binds the tyrosine kinase CSK through a P1 motif. LYP dephosphorylates activating tyrosines of Lck, Fyn, and ZAP-70, setting negative thresholds for T and B cell receptor signaling. The R620W variant, which disrupts CSK binding, is one of the strongest common genetic risk factors for autoimmune disease, associated with type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Unlike the signal-promoting SHP-2, LYP functions as a brake on immunity, and PTPN22 is being pursued as a target for immunomodulatory therapy.
