PDCD1
This gene encodes a cell surface membrane protein of the immunoglobulin superfamily. This protein is expressed in pro-B-cells and is thought to play a role in their differentiation. In mice, expression of this gene is induced in the thymus when anti-CD3 antibodies are injected and large numbers of thymocytes undergo apoptosis. Mice deficient for this gene bred on a BALB/c background developed dilated cardiomyopathy and died from congestive heart failure. These studies suggest that this gene product may also be important in T cell function and contribute to the prevention of autoimmune diseases. [provided by RefSeq, Jul 2008]
Full Name
Programmed Cell Death 1
Function
Inhibitory receptor on antigen activated T-cells that plays a critical role in induction and maintenance of immune tolerance to self (PubMed:21276005).
Delivers inhibitory signals upon binding to ligands CD274/PDCD1L1 and CD273/PDCD1LG2 (PubMed:21276005).
Following T-cell receptor (TCR) engagement, PDCD1 associates with CD3-TCR in the immunological synapse and directly inhibits T-cell activation (By similarity).
Suppresses T-cell activation through the recruitment of PTPN11/SHP-2: following ligand-binding, PDCD1 is phosphorylated within the ITSM motif, leading to the recruitment of the protein tyrosine phosphatase PTPN11/SHP-2 that mediates dephosphorylation of key TCR proximal signaling molecules, such as ZAP70, PRKCQ/PKCtheta and CD247/CD3zeta (By similarity).
The PDCD1-mediated inhibitory pathway is exploited by tumors to attenuate anti-tumor immunity and escape destruction by the immune system, thereby facilitating tumor survival (PubMed:28951311).
The interaction with CD274/PDCD1L1 inhibits cytotoxic T lymphocytes (CTLs) effector function (PubMed:28951311).
The blockage of the PDCD1-mediated pathway results in the reversal of the exhausted T-cell phenotype and the normalization of the anti-tumor response, providing a rationale for cancer immunotherapy (PubMed:22658127, PubMed:25034862, PubMed:25399552).
Biological Process
Adaptive immune responseIEA:UniProtKB-KW
Apoptotic processManual Assertion Based On ExperimentTAS:ProtInc
Humoral immune responseManual Assertion Based On ExperimentTAS:ProtInc
Multicellular organism developmentManual Assertion Based On ExperimentTAS:ProtInc
Negative regulation of apoptotic processIEA:Ensembl
Negative regulation of immune responseISS:UniProtKB
Negative regulation of tolerance inductionIEA:Ensembl
Positive regulation of T cell apoptotic processManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of immune responseManual Assertion Based On ExperimentIBA:GO_Central
Cellular Location
Cell membrane
Involvement in disease
Systemic lupus erythematosus 2 (SLEB2):
A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow.
Topology
Extracellular: 24-170
Helical: 171-191
Cytoplasmic: 192-288
PTM
Ubiquitinated at Lys-233 by the SCF(FBXO38) complex, leading to its proteasomal degradation (PubMed:30487606).
Ubiquitinated via 'Lys-48'-linked polyubiquitin chains (PubMed:30487606).
Tyrosine phosphorylated at Tyr-223 (within ITIM motif) and Tyr-248 (ITSM motif) upon ligand binding. Phosphorylation at Tyr-248 promotes the recruitment of the protein tyrosine phosphatase PTPN11/SHP-2 that mediates dephosphorylation of key TCR proximal signaling molecules, such as ZAP70, PRKCQ/PKCtheta and CD247/CD3zeta.
N-glycosylation at Asn-58 contains at least two N-acetylglucosamine units and one fucose (PubMed:28165004).
N-glycosylation does not affect binding to nivolumab drug (PubMed:28165004).
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