PTPN6

Domain

The N-terminal SH2 domain functions as an auto-inhibitory domain, blocking the catalytic domain in the ligand-free close conformation.

Function

Tyrosine phosphatase enzyme that plays important roles in controlling immune signaling pathways and fundamental physiological processes such as hematopoiesis (PubMed:14739280, PubMed:29925997). Dephosphorylates and negatively regulate several receptor tyrosine kinases (RTKs) such as EGFR, PDGFR and FGFR, thereby modulating their signaling activities (PubMed:21258366, PubMed:9733788). When recruited to immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptors such as immunoglobulin-like transcript 2/LILRB1, programmed cell death protein 1/PDCD1, CD3D, CD22, CLEC12A and other receptors involved in immune regulation, initiates their dephosphorylation and subsequently inhibits downstream signaling events (PubMed:11907092, PubMed:14739280, PubMed:37932456, PubMed:38166031). Modulates the signaling of several cytokine receptors including IL-4 receptor (PubMed:9065461). Additionally, targets multiple cytoplasmic signaling molecules including STING1, LCK or STAT1 among others involved in diverse cellular processes including modulation of T-cell activation or cGAS-STING signaling (PubMed:34811497, PubMed:38532423). Within the nucleus, negatively regulates the activity of some transcription factors such as NFAT5 via direct dephosphorylation. Acts also as a key transcriptional regulator of hepatic gluconeogenesis by controlling recruitment of RNA polymerase II to the PCK1 promoter together with STAT5A (PubMed:37595871).

Post-translational modifications

Phosphorylated on tyrosine residues. Binding of KITLG/SCF to KIT increases tyrosine phosphorylation (By similarity). Phosphorylation at Tyr-564 by LYN enhances phosphatase activity. Phosphorylation at Thr-394 by TAOK3 leads to polyubiquitination and subsequent proteasomal degradation (PubMed:38166031).

Ubiquitinated after phosphorylation by TAOK3 (PubMed:38166031). Ubiquitinated by a cooperation between ITCH and WWP2 via 'Lys-27'-mediated polyubiquitin chains resulting in the reduction of its association with LCK (PubMed:29925997).

Sequence similarities

Belongs to the protein-tyrosine phosphatase family. Non-receptor class 2 subfamily.

Tissue specificity

Isoform 1 is expressed in hematopoietic cells. Isoform 2 is expressed in non-hematopoietic cells.

Cellular localization

• Cytoplasm
• Nucleus
• In neurons, translocates into the nucleus after treatment with angiotensin II (By similarity). Shuttles between the cytoplasm and nucleus via its association with PDPK1.

Alternative names

• HCP
• PTP1C
• PTPN6
• HCP
• PTP1C
• Tyrosine-protein phosphatase non-receptor type 6
• Hematopoietic cell protein-tyrosine phosphatase
• Protein-tyrosine phosphatase 1C
• Protein-tyrosine phosphatase SHP-1
• SH-PTP1
• PTP-1C

Database links

• entrezGene:5777
• omim:176883
• swissprot:P29350

Target type

Proteins

Primary research area

Immunology & Infectious Disease

Other research areas

• Immuno-oncology

Molecular weight

67561Da