Affinage

PTPRM

Receptor-type tyrosine-protein phosphatase mu · UniProt P28827

Length
1452 aa
Mass
163.7 kDa
Annotated
2026-06-10
14 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTPRM is a receptor-type transmembrane protein tyrosine phosphatase that couples homophilic cell-cell adhesion to negative regulation of tyrosine-phosphorylation-dependent growth signaling (PMID:31900385, PMID:36436563). Through its extracellular domain, PTPRM forms rigid, extended head-to-tail homodimers that mediate homophilic trans adhesion between adjacent cell membranes, with binding specificity dictated by discrete interface residues that distinguish it from paralogs such as PTPRK (PMID:36436563). Functionally, PTPRM directly binds STAT3 and dephosphorylates it at Y705 to suppress STAT3 activation, an interaction abolished by the STAT3 Y705F mutation and competitively blocked when DDIAS occupies the STAT3 transactivation domain (PMID:31900385). PTPRM acts as a tumor suppressor that restrains cell growth and colony formation in colorectal and neuroendocrine tumor cells, and in the neuroendocrine context this growth inhibition proceeds independently of its phosphatase catalytic activity (PMID:25910225, PMID:31349215). PTPRM additionally restrains ERK1/2 signaling in keratinocytes, where its downregulation drives proliferation (PMID:36139479). Its expression is silenced by upstream epigenetic regulators: BMI1 binds the PTPRM promoter and drives chromatin remodeling in spermatogonia (PMID:34739857), and FN1 induces PTPRM promoter methylation in glioblastoma, relieving suppression of STAT3 phosphorylation (PMID:34225581).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1993 Medium

    Establishing the chromosomal location of PTPRM (then PTPRL1) provided the genomic anchor needed to link the gene to subsequent functional and disease studies.

    Evidence FISH with a genomic clone mapping the gene to 18p11.2

    PMID:8404049

    Open questions at the time
    • No functional or mechanistic information about the encoded protein
    • Mapping alone does not define expression pattern or activity
  2. 2015 Medium

    Defining PTPRM as a tumor suppressor in colorectal cancer answered whether loss of this phosphatase has oncogenic consequences and identified promoter hypermethylation as a silencing route.

    Evidence Copy number analysis, promoter methylation analysis, and colony-formation/growth assays in colorectal cancer cells

    PMID:25910225

    Open questions at the time
    • Direct substrate or signaling pathway mediating growth suppression not defined
    • Single lab
    • Causal link between methylation and phenotype correlative
  3. 2019 Medium

    Testing a phosphatase-dead mutant showed that PTPRM can suppress neuroendocrine tumor cell growth without its catalytic activity, revealing a phosphatase-independent tumor-suppressive mode.

    Evidence Overexpression and phosphatase-dead mutant assays with colony-formation, proliferation, and apoptosis readouts in SI-NET cell lines

    PMID:31349215

    Open questions at the time
    • The non-catalytic mechanism (e.g. adhesion or scaffolding) not identified
    • Context-specificity versus catalytic roles elsewhere unresolved
  4. 2020 High

    Identifying STAT3 Y705 as a direct PTPRM substrate, and DDIAS as a competitive blocker, defined the molecular basis by which PTPRM restrains STAT3 signaling and how tumors evade it.

    Evidence PTP siRNA library screen, reciprocal endogenous Co-IP, STAT3 Y705F binding assay, and knockdown/overexpression with phospho-STAT3 readout in lung cancer cells

    PMID:31900385

    Open questions at the time
    • Whether STAT3 is the principal substrate across tissues not established
    • Structural basis of the PTPRM-STAT3 TAD interaction not resolved
  5. 2021 Medium

    Placing PTPRM downstream of BMI1 and FN1 connected upstream epigenetic regulators to its silencing in spermatogonia and glioblastoma, explaining how PTPRM tumor-suppressive function is lost.

    Evidence ChIP and Bmi1-KO rescue in spermatogonia (GC-1 cells); methylation-specific PCR, FN1/PTPRM knockdown-overexpression, and 5-aza rescue with phospho-STAT3 readout in glioblastoma

    PMID:34225581 PMID:34739857

    Open questions at the time
    • Direct demonstration that BMI1-driven remodeling and FN1-driven methylation act on the same regulatory elements not shown
    • Both rely on single-lab datasets
  6. 2022 High

    Structural analysis of the extracellular domain established the molecular geometry of PTPRM homophilic adhesion and pinpointed an interface residue governing paralog specificity.

    Evidence X-ray crystallography of N-terminal domains, SAXS of full-length ECDs of PTPRM and PTPRK, and W351G mutagenesis with dimerization assay

    PMID:36436563

    Open questions at the time
    • How extracellular adhesion couples to intracellular phosphatase activity not established
    • Functional consequence of adhesion in tissue context not measured here
  7. 2022 Medium

    Linking PTPRM downregulation to excessive ERK1/2 signaling in keratinocytes extended its growth-restraining role to epidermal proliferation and psoriasis biology.

    Evidence Microarray profiling, EMSA for NF-kB and Sp1 binding, and RSK inhibition in a 3D psoriatic skin model

    PMID:36139479

    Open questions at the time
    • Direct phosphatase substrate in the ERK pathway not identified
    • Causality between PTPRM loss and ERK hyperactivation correlative
  8. 2022 Low

    Identifying PTPRM as a zinc-regulated mediator of synapse formation raised a neuronal role distinct from its tumor-suppressive activity.

    Evidence Cultured neuron system with zinc manipulation, synapse formation and synaptic transmission assays, genetic identification of PTPRM

    PMID:35386272

    Open questions at the time
    • Single lab with limited methodological detail; mechanism of zinc regulation not defined
    • Direct molecular link between PTPRM and synaptic substrates absent
  9. 2024 Low

    Observing elevated STAT3 phosphorylation and Th17 fractions in PTPRM-hemizygous 18p deletion patients suggested the STAT3-suppressing role operates in human immune cells.

    Evidence Chromosomal microarray, whole genome sequencing, phospho-STAT3 assay, and Th17 immunophenotyping in monozygotic triplets

    PMID:39359478

    Open questions at the time
    • Observational case series of three patients without direct PTPRM manipulation
    • Hemizygosity confounds attribution to PTPRM specifically

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PTPRM extracellular homophilic adhesion is mechanistically coupled to its intracellular phosphatase activity and substrate selection across tissues remains unresolved.
  • No structure of the full receptor linking ECD engagement to catalytic state
  • Substrate repertoire beyond STAT3 uncharacterized
  • Mechanism of phosphatase-independent growth suppression unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 1 GO:0098631 cell adhesion mediator activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1500931 Cell-Cell communication 1
Partners
DDIASSTAT3

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 PTPRM directly interacts with STAT3 and dephosphorylates STAT3 at Y705. PTPRM bound wild-type STAT3 but not the STAT3 Y705F mutant. DDIAS competes with PTPRM for binding to the STAT3 transactivation domain (TAD), thereby preventing PTPRM-mediated STAT3 dephosphorylation and sustaining STAT3 activation in lung cancer cells. siRNA PTP library screening, Co-immunoprecipitation of endogenous proteins, STAT3 Y705F mutant binding assay, PTPRM knockdown/overexpression with phospho-STAT3 readout Oncogenesis High 31900385
2021 BMI1 binds to the promoter region of the PTPRM gene and drives chromatin remodeling to silence PTPRM expression in spermatogonia. Knockdown of PTPRM rescued proliferation defects in BMI1-deficient cells, placing PTPRM downstream of BMI1 in a spermatogonia maintenance pathway. ChIP (BMI1 binding to PTPRM promoter), Bmi1-knockout mouse model, siRNA knockdown of Ptprm in GC-1 cells, proliferation and apoptosis assays Biochemical and biophysical research communications Medium 34739857
2015 PTPRM negatively regulates cell growth and colony formation in colorectal cancer cells. Loss of PTPRM function via loss of heterozygosity and promoter hypermethylation promotes oncogenic cell growth, supporting a tumor suppressor role. Genomic copy number analysis (oligonucleotide microarray), qPCR, functional overexpression/loss-of-function assays (colony formation, cell growth), promoter methylation analysis Scientific reports Medium 25910225
2021 FN1 upregulation increases PTPRM promoter methylation, reducing PTPRM expression and thereby relieving inhibition of STAT3 phosphorylation to promote glioblastoma cell proliferation. Knockdown of FN1 decreased PTPRM methylation and inhibited STAT3 phosphorylation. Treatment with the demethylating agent 5-aza restored PTPRM expression and reduced p-STAT3. Methylation-specific PCR, lentiviral overexpression/knockdown of FN1 and PTPRM, phospho-STAT3 immunoblotting, 5-aza demethylation treatment, colony formation and cell viability assays Pharmaceutical biology Medium 34225581
2022 Downregulation of PTPRM in psoriatic skin promotes keratinocyte proliferation through excessive ERK1/2 signaling, with increased DNA-binding activity of downstream NF-κB and Sp1 transcription factors observed under psoriatic conditions. Gene profiling on microarrays in 3D psoriatic skin model, electrophoretic mobility shift assay (EMSA) for NF-κB and Sp1 binding, RSK inhibition experiments Cells Medium 36139479
2022 PTPRM is a critical gene for synapse formation regulated by zinc ions. Zinc ion availability modulates synapse formation and synaptic transmission in cultured neurons, and PTPRM mediates this effect. Cultured neuron system, zinc ion manipulation, synapse formation assays, synaptic transmission measurements, PTPRM genetic identification as key mediator Frontiers in molecular neuroscience Low 35386272
2022 PTPRM forms head-to-tail homodimers via its extracellular domain (ECD), mediating homophilic trans cell adhesion between adjacent cell membranes. Solution SAXS revealed that the full-length ECD of PTPRM is a rigid extended molecule. A single residue difference (W351 in PTPRK vs. glycine in PTPRM) within the interaction interface is a determinant of homophilic specificity, as mutation of W351 to glycine abolishes PTPRK dimer formation in vitro. X-ray crystallography of PTPRK N-terminal domains, small-angle X-ray scattering (SAXS) of full-length ECDs of PTPRM and PTPRK, in vitro mutagenesis (W351G) with dimerization assay The Journal of biological chemistry High 36436563
2019 Overexpression of PTPRM in SI-NET cell lines reduced cell growth and proliferation and induced apoptosis. Notably, the tyrosine phosphatase activity of PTPRM was NOT required for cell growth inhibition in this context, suggesting a phosphatase-independent mechanism. PTPRM overexpression in CNDT2.5 and KRJ-I SI-NET cell lines, colony formation assay, cell proliferation assay, apoptosis assay; phosphatase-dead mutant experiments Endocrine connections Medium 31349215
1993 The human PTPRM gene (formerly PTPRL1) was mapped to chromosomal band 18p11.2 by fluorescence in situ hybridization using a genomic clone. Fluorescence in situ hybridization (FISH) with genomic clone Cytogenetics and cell genetics Medium 8404049
2024 PTPRM hemizygosity in 18p deletion syndrome was associated with increased STAT3 phosphorylation and elevated Th17 cell fractions, consistent with PTPRM functioning as a negative regulator of STAT3 through dephosphorylation in immune cells. However, this is based on a single case series and hemizygosity rather than direct genetic manipulation. Chromosomal microarray and whole genome sequencing in monozygotic triplets, phospho-STAT3 assay, Th17 cell fraction analysis by immunophenotyping Frontiers in genetics Low 39359478

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 DDIAS promotes STAT3 activation by preventing STAT3 recruitment to PTPRM in lung cancer cells. Oncogenesis 36 31900385
2021 BMI1 promotes spermatogonia proliferation through epigenetic repression of Ptprm. Biochemical and biophysical research communications 27 34739857
2020 PSMD11, PTPRM and PTPRB as novel biomarkers of pancreatic cancer progression. Biochimica et biophysica acta. General subjects 24 32663515
2015 Loss of PTPRM associates with the pathogenic development of colorectal adenoma-carcinoma sequence. Scientific reports 21 25910225
2019 PTPRM, a candidate tumor suppressor gene in small intestinal neuroendocrine tumors. Endocrine connections 17 31349215
2022 CircRNA PTPRM Promotes Non-Small Cell Lung Cancer Progression by Modulating the miR-139-5p/SETD5 Axis. Technology in cancer research & treatment 13 35491723
2022 Gene Profiling of a 3D Psoriatic Skin Model Enriched in T Cells: Downregulation of PTPRM Promotes Keratinocyte Proliferation through Excessive ERK1/2 Signaling. Cells 12 36139479
2021 PTPRM methylation induced by FN1 promotes the development of glioblastoma by activating STAT3 signalling. Pharmaceutical biology 12 34225581
2022 PTPRM Is Critical for Synapse Formation Regulated by Zinc Ion. Frontiers in molecular neuroscience 11 35386272
1993 Fine mapping of the human receptor-like protein tyrosine phosphatase gene (PTPRM) to 18p11.2 by fluorescence in situ hybridization. Cytogenetics and cell genetics 6 8404049
2022 Characterization of Poorly Cohesive and Signet Ring Cell Carcinomas and Identification of PTPRM as a Diagnostic Marker. Cancers 3 35626106
2022 Determinants of receptor tyrosine phosphatase homophilic adhesion: Structural comparison of PTPRK and PTPRM extracellular domains. The Journal of biological chemistry 3 36436563
2024 Monozygotic triplets with juvenile-onset autoimmunity and 18p microdeletion involving PTPRM. Frontiers in genetics 2 39359478
2023 A quantitative trait GWAS on lens thickness identifies novel risk loci on PTPRM in the narrow angle individuals susceptible to PACG. European journal of ophthalmology 2 36927043

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