Phospho-SHP1 (Tyr564) is the activated tyrosine-phosphorylated form of SHP1 (PTPN6), a hematopoietic-specific non-receptor protein tyrosine phosphatase. This C-terminal Tyr564 residue is phosphorylated primarily by Lyn and other Src-family kinases upon cytokine or immune receptor stimulation. The modification triggers intramolecular binding with SHP1's C-SH2 domain, relieving autoinhibition and boosting catalytic phosphatase activity. It targets STAT5, IL-3Rβ and EPOR to restrain proliferative and inflammatory signaling in myeloid and lymphoid cells. Loss of Tyr564 phosphorylation causes persistent STAT5 hyperactivation, driving myeloproliferative neoplasms such as CMML. It acts as a vital negative immune checkpoint, linking its abundance to leukemia progression and autoimmune inflammatory disorders. (PMID: 20858858, 38203502)