SHP1

SHP-1, also known as SHP-1 protein tyrosine phosphatase or PTPN6, is a non-receptor protein tyrosine phosphatase expressed primarily in hematopoietic cells. It functions as a negative regulator of signaling pathways that control immune cell activation and inflammation. The protein contains two Src homology 2 (SH2) domains at its N-terminus and a C-terminal catalytic protein tyrosine phosphatase (PTP) domain. The SH2 domains regulate catalytic activity through autoinhibition and mediate recruitment to phosphorylated immunoreceptors.

SHP-1 is recruited to phosphorylated immunoreceptors bearing immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and to other phosphotyrosine-containing adapters. Once localized to these sites, SHP-1 dephosphorylates a range of substrates, including kinases and adaptor proteins, thereby dampening signaling cascades. Substrates and pathways commonly affected include Syk and Zap-70 in lymphocytes, Src family kinases, PLCγ, PI3K, and components of the JAK/STAT axis. Through these actions, SHP-1 modulates receptor-mediated signaling from the T cell receptor, B cell receptor, cytokine receptors, and other immune receptors, contributing to the attenuation of activation, regulation of cytokine production, and maintenance of immune tolerance.

SHP-1 is encoded by the PTPN6 gene. In mice, loss-of-function mutations give rise to the motheaten and viable motheaten syndromes, with severe autoimmune and inflammatory phenotypes, underscoring SHP-1’s importance in immune homeostasis. In humans, SHP-1 activity or expression can be altered in certain diseases and cancers, and the phosphatase has been investigated as a potential target for therapies aiming to modulate immune signaling.