Affinage

ITPRIPL1

Inositol 1,4,5-trisphosphate receptor-interacting protein-like 1 · UniProt Q6GPH6

Length
555 aa
Mass
63.4 kDa
Annotated
2026-04-28
57 papers in source corpus 2 papers cited in narrative 2 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ITPRIPL1 (also termed CD3L1) is a cell-surface inhibitory ligand that binds CD3ε on T cells through its extracellular domain, suppressing the initial phase of T cell activation by reducing calcium influx and ZAP70 phosphorylation (PMID:38614099). ITPRIPL1 is overexpressed in non-small cell lung cancer, where its expression inversely correlates with CD8+ T cell infiltration, consistent with a role in tumor immune evasion (PMID:38188019). Neutralizing antibodies against ITPRIPL1 restore T cell infiltration and suppress tumor growth in vivo, establishing it as a functional immune checkpoint (PMID:38614099).

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2023 Medium

    Establishing that ITPRIPL1 is aberrantly expressed in human tumors and inversely associated with cytotoxic T cell presence provided the first clinical correlate suggesting an immunosuppressive role for this previously uncharacterized protein.

    Evidence Immunohistochemistry on NSCLC patient tissue with correlation to CD8+ T cell density

    PMID:38188019

    Open questions at the time
    • Correlative IHC without functional manipulation; does not prove causality
    • Limited to one tumor type (NSCLC)
    • No mechanistic target on T cells identified
  2. 2024 High

    Identification of CD3ε as the direct binding partner of ITPRIPL1 and demonstration that this interaction suppresses proximal TCR signaling (calcium influx, ZAP70 phosphorylation) defined ITPRIPL1 as a bona fide inhibitory immune checkpoint ligand and showed that its blockade restores antitumor immunity in vivo.

    Evidence Co-immunoprecipitation/binding assays, calcium flux measurements, ZAP70 phosphorylation assays, neutralizing antibody treatment in mouse tumor models with canine clinical validation

    PMID:38614099

    Open questions at the time
    • Structural basis of the ITPRIPL1–CD3ε interaction is unresolved
    • Whether ITPRIPL1 signals bidirectionally into the expressing cell is unknown
    • Relative contribution of ITPRIPL1 versus PD-L1 and other checkpoints in different tumor contexts not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural determinants of the ITPRIPL1–CD3ε interface, the breadth of tumor types dependent on this checkpoint, and whether ITPRIPL1 blockade synergizes with existing immunotherapies remain to be defined.
  • No crystal or cryo-EM structure of the ITPRIPL1–CD3ε complex
  • No systematic pan-cancer functional studies
  • Combination therapy with anti-PD-1/PD-L1 not formally tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 2 GO:0005886 plasma membrane 1 R-HSA-162582 Signal Transduction 1
Partners
CD3E

Evidence

Reading pass · 2 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2024 ITPRIPL1 functions as an inhibitory ligand of CD3ε on T cells; its extracellular domain binds CD3ε and significantly decreases calcium influx and ZAP70 phosphorylation, thereby impeding initial T cell activation ('signal one') and enabling tumor immune evasion. Co-immunoprecipitation/binding assays, calcium influx assays, ZAP70 phosphorylation assays, neutralizing antibody treatment in mouse tumor models Cell High 38614099
2023 ITPRIPL1 is overexpressed in non-small cell lung cancer tissue and its expression is negatively correlated with CD8+ T cell infiltration, consistent with its role as an immune checkpoint ligand suppressing T cell activity in the tumor microenvironment. Immunohistochemistry with anti-ITPRIPL1 monoclonal antibody on NSCLC patient tissue samples; correlation analysis with anti-CD8 staining Frontiers in cell and developmental biology Medium 38188019

Source papers

Stage 0 corpus · 57 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 An alternatively spliced cyclin D1 isoform, cyclin D1b, is a nuclear oncogene. Cancer research 210 14612495
1994 High agonist-independent activity is a distinguishing feature of the dopamine D1B receptor subtype. The Journal of biological chemistry 194 7525564
2006 Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation. Proceedings of the National Academy of Sciences of the United States of America 103 16461912
2008 Alteration of cyclin D1 transcript elongation by a mutated transcription factor up-regulates the oncogenic D1b splice isoform in cancer. Proceedings of the National Academy of Sciences of the United States of America 85 18413612
2012 A tandem segmental duplication (TSD) in green revolution gene Rht-D1b region underlies plant height variation. The New phytologist 67 22849513
2001 Phospholipase D1b and D2a generate structurally identical phosphatidic acid species in mammalian cells. The Biochemical journal 67 11736663
1994 D1A, D1B, and D1C dopamine receptors from Xenopus laevis. Proceedings of the National Academy of Sciences of the United States of America 65 7937989
1993 Cloning and characterization of the opossum kidney cell D1 dopamine receptor: expression of identical D1A and D1B dopamine receptor mRNAs in opossum kidney and brain. Molecular pharmacology 65 8246914
2002 Antigen-stimulated activation of phospholipase D1b by Rac1, ARF6, and PKCalpha in RBL-2H3 cells. Molecular biology of the cell 64 11950936
2010 Identification of ASF/SF2 as a critical, allele-specific effector of the cyclin D1b oncogene. Cancer research 62 20460515
2006 The cyclin D1b splice variant: an old oncogene learns new tricks. Cell division 61 16863592
2008 Cyclin D1b is aberrantly regulated in response to therapeutic challenge and promotes resistance to estrogen antagonists. Cancer research 59 18632615
1997 Early emergence of three dopamine D1 receptor subtypes in vertebrates. Molecular phylogenetic, pharmacological, and functional criteria defining D1A, D1B, and D1C receptors in European eel Anguilla anguilla. The Journal of biological chemistry 58 9006917
1999 Immunoblot and immunohistochemical comparison of murine monoclonal antibodies specific for the rat D1a and D1b dopamine receptor subtypes. Journal of neuroimmunology 49 10580800
1997 Cellular distribution of the rat D1B receptor in central nervous system using anti-receptor antisera. Brain research 47 9037493
1996 Silencing of the constitutive activity of the dopamine D1B receptor. Reciprocal mutations between D1 receptor subtypes delineate residues underlying activation properties. The Journal of biological chemistry 46 8910419
2024 ITPRIPL1 binds CD3ε to impede T cell activation and enable tumor immune evasion. Cell 39 38614099
2017 Anti-oncogenic activities of cyclin D1b siRNA on human bladder cancer cells via induction of apoptosis and suppression of cancer cell stemness and invasiveness. International journal of oncology 38 29115414
2011 PACSIN 2 represses cellular migration through direct association with cyclin D1 but not its alternate splice form cyclin D1b. Cell cycle (Georgetown, Tex.) 38 21200149
2001 Quantification of D1B(D5) receptors in dopamine D1A receptor-deficient mice. Synapse (New York, N.Y.) 38 11169782
1994 Characteristics of stably expressed human dopamine D1a and D1b receptors: atypical behavior of the dopamine D1b receptor. European journal of pharmacology 37 8206133
2000 Localization of dopamine D1A and D1B receptor mRNAs in the forebrain and midbrain of the domestic chick. Journal of chemical neuroanatomy 35 11036238
1993 Molecular cloning, stable expression and desensitization of the human dopamine D1b/D5 receptor. Journal of receptor research 29 8450505
2009 Cyclin D1b variant promotes cell invasiveness independent of binding to CDK4 in human bladder cancer cells. Molecular carcinogenesis 28 19415719
2010 Cyclin D1b in human breast carcinoma and coexpression with cyclin D1a is associated with poor outcome. Anticancer research 27 20530440
2006 Relevance of cyclin D1b expression and CCND1 polymorphism in the pathogenesis of multiple myeloma and mantle cell lymphoma. BMC cancer 27 17022831
2014 Cyclin D1b splice variant promotes αvβ3-mediated adhesion and invasive migration of breast cancer cells. Cancer letters 26 25193465
1997 Molecular identification of a dopamine D1b receptor in bovine retinal pigment epithelium. Neuroscience letters 24 9406867
2021 Effect of gibberellin-sensitive Rht18 and gibberellin-insensitive Rht-D1b dwarfing genes on vegetative and reproductive growth in bread wheat. Journal of experimental botany 22 33070174
2012 Expression of cyclin D1a and D1b as predictive factors for treatment response in colorectal cancer. British journal of cancer 21 23099809
2002 Detecting protein-phospholipid interactions. Epidermal growth factor-induced activation of phospholipase D1b in situ. The Journal of biological chemistry 20 11950840
2011 Knocking down cyclin D1b inhibits breast cancer cell growth and suppresses tumor development in a breast cancer model. Cancer science 17 21521417
2021 Automatic Detection of the Circulating Cell-Free Methylated DNA Pattern of GCM2, ITPRIPL1 and CCDC181 for Detection of Early Breast Cancer and Surgical Treatment Response. Cancers 16 33803633
2015 Consequence of the tumor-associated conversion to cyclin D1b. EMBO molecular medicine 16 25787974
2010 Cyclin D1b represses breast cancer cell growth by antagonizing the action of cyclin D1a on estrogen receptor alpha-mediated transcription. International journal of oncology 16 19956831
2010 Cyclin K and cyclin D1b are oncogenic in myeloma cells. Molecular cancer 16 20459741
2002 Autocrine activation of adenosine A1 receptors blocks D1A but not D1B dopamine receptor desensitization. Journal of neurochemistry 16 12354303
2005 The relative levels of cyclin D1a and D1b alternative transcripts in mantle cell lymphoma may depend more on sample origin than on CCND1 polymorphism. Haematologica 14 15951302
2000 Differential expression of D(1A) and D(1B) dopamine receptor mRNAs in the developing avian retina. Journal of neurochemistry 14 10936188
1998 Dopamine D1B receptor chimeras reveal modulation of partial agonist activity by carboxyl-terminal tail sequences. Journal of neurochemistry 14 9832160
2018 Cyclin D1b Splice Variant Promotes αvβ3-mediated EMT Induced by LPS in Breast Cancer Cells. Current medical science 13 30074214
2004 Delineation of the conserved functional properties of D1A, D1B and D1C dopamine receptor subtypes in vertebrates. Biology of the cell 13 15207908
2016 Akt-dependent activation of Erk by cyclin D1b contributes to cell invasiveness and tumorigenicity. Oncology letters 11 28105192
2014 Cyclin D1b overexpression inhibits cell proliferation and induces cell apoptosis in cervical cancer cells in vitro and in vivo. International journal of clinical and experimental pathology 11 25120779
2009 Enhanced skin carcinogenesis and lack of thymus hyperplasia in transgenic mice expressing human cyclin D1b (CCND1b). Molecular carcinogenesis 10 18942117
2023 Meiotic instability and irregular chromosome pairing underpin heat-induced infertility in bread wheat carrying the Rht-B1b or Rht-D1b Green Revolution genes. The New phytologist 9 37691304
2013 Female-specific rectal carcinogenesis in cyclin D1b transgenic mice. Carcinogenesis 9 23975835
2012 New cis-regulatory elements in the Rht-D1b locus region of wheat. Functional & integrative genomics 9 22592657
2008 Identification of the cyclin D1b mRNA variant in mouse. Molecular biology reports 9 18446443
1992 Eyespot resistance gene Pch-1 in H-93 wheat lines. Evidence of linkage to markers of chromosome group 7 and resolution from the endopeptidase locus Ep-D1b. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 9 24202933
2023 Development of a monoclonal antibody to ITPRIPL1 for immunohistochemical diagnosis of non-small cell lung cancers: accuracy and correlation with CD8+ T cell infiltration. Frontiers in cell and developmental biology 5 38188019
1995 Glucocorticoids inhibit D1B, but not D2, receptor-mediated effects on hypothalamic atrial natriuretic factor neurons. Endocrinology 5 7588310
2003 Dopamine as a novel anti-migration factor of vascular smooth muscle cells through D1A and D1B receptors. Journal of cardiovascular pharmacology 4 12688394
2023 Role of Cyclin D1b in Inducing Macrophages Toward a Tumor-associated Macrophage-like Phenotype in Murine Breast Cancer. Current medical science 3 37391677
2024 Two dwarfing genes Rht-B1b and Rht-D1b show pleiotropic effects on grain protein content in bread wheat (Triticum aestivum L.). TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 2 39141110
2025 Population transcriptome and phenotype analyses reveal that Rht-D1b contributed a larger seedling root to modern bread wheat. The Plant cell 1 41205820
2001 Rat pancreatic acinar cells express a cytosolic phospholipase D1b isoform that is not regulated by cholecystokinin. Pflugers Archiv : European journal of physiology 1 11680625