Details for: GZMM

Gene ID: 3004

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: GZMM

Ensembl ID: ENSG00000197540

Description: granzyme M

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • CD16-positive, CD56-dim natural killer cell, human CL0000939
    CSI 102.6
    rCSI 68.38%
    PRS 86.22
  • CD16-negative, CD56-bright natural killer cell, human CL0000938
    CSI 63.41
    rCSI 47.55%
    PRS 91.3
  • central memory CD8-positive, alpha-beta T cell CL0000907
    CSI 49.8
    rCSI 33.55%
    PRS 83.37
  • activated type II NK T cell CL0000931
    CSI 30.93
    rCSI 34.81%
    PRS 85.36
  • naive T cell CL0000898
    CSI 26.48
    rCSI 18.43%
    PRS 84.75
  • CD4-positive, alpha-beta memory T cell CL0000897
    CSI 23.87
    rCSI 17.13%
    PRS 83.69
  • gamma-delta T cell CL0000798
    CSI 20.39
    rCSI 23.94%
    PRS 89.38
  • activated CD4-positive, alpha-beta T cell CL0000896
    CSI 16.53
    rCSI 15.28%
    PRS 87.29
  • effector CD8-positive, alpha-beta T cell CL0001050
    CSI 15.17
    rCSI 11.54%
    PRS 82.89
  • mucosal invariant T cell CL0000940
    CSI 13.53
    rCSI 10.93%
    PRS 80.43
  • double negative thymocyte CL0002489
    CSI 13.53
    rCSI 9.4%
    PRS 81.68
  • naive thymus-derived CD8-positive, alpha-beta T cell CL0000900
    CSI 11.91
    rCSI 8.37%
    PRS 86.44
  • CD4-positive, alpha-beta thymocyte CL0000810
    CSI 11.39
    rCSI 9.13%
    PRS 87.26
  • CD4-positive, alpha-beta cytotoxic T cell CL0000934
    CSI 10.91
    rCSI 14.98%
    PRS 87.64
  • mononuclear phagocyte CL0000113
    CSI 9.94
    rCSI 21.88%
    PRS 74.3
  • effector memory CD8-positive, alpha-beta T cell CL0000913
    CSI 9.73
    rCSI 8.86%
    PRS 83.63
  • CD8-positive, alpha-beta cytotoxic T cell CL0000794
    CSI 9.35
    rCSI 11.16%
    PRS 87.42
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 8.67
    rCSI 10.51%
    PRS 53.92
  • mature T cell CL0002419
    CSI 8.55
    rCSI 6.65%
    PRS 86.31
  • intraepithelial lymphocyte CL0002496
    CSI 8.36
    rCSI 22.77%
    PRS 92.27
  • effector CD4-positive, alpha-beta T cell CL0001044
    CSI 8.21
    rCSI 23.55%
    PRS 88.35
  • T cell CL0000084
    CSI 7.87
    rCSI 15.39%
    PRS 92.05
  • mature NK T cell CL0000814
    CSI 7.87
    rCSI 10.06%
    PRS 85.96
  • effector memory CD8-positive, alpha-beta T cell, terminally differentiated CL0001062
    CSI 7.73
    rCSI 38.77%
    PRS 82.58
  • T follicular helper cell CL0002038
    CSI 7.66
    rCSI 5.73%
    PRS 84.1
  • activated CD8-positive, alpha-beta T cell CL0000906
    CSI 7.25
    rCSI 7.13%
    PRS 87.25
  • CD4-positive helper T cell CL0000492
    CSI 6.8
    rCSI 5.15%
    PRS 83.31
  • CD4-positive, CD25-positive, alpha-beta regulatory T cell CL0000792
    CSI 6.65
    rCSI 6.53%
    PRS 84.83
  • natural killer cell CL0000623
    CSI 6.54
    rCSI 12.68%
    PRS 86.52
  • CD8-positive, alpha-beta memory T cell CL0000909
    CSI 6.11
    rCSI 6.38%
    PRS 87.69
  • naive thymus-derived CD4-positive, alpha-beta T cell CL0000895
    CSI 5.03
    rCSI 6.33%
    PRS 90.59
  • central memory CD4-positive, alpha-beta T cell CL0000904
    CSI 3.98
    rCSI 2.35%
    PRS 86.47
  • T-helper 1 cell CL0000545
    CSI 3.37
    rCSI 6.09%
    PRS 88.61
  • erythrocyte CL0000232
    CSI 2.85
    rCSI 6.47%
    PRS 72.32
  • memory T cell CL0000813
    CSI 2.69
    rCSI 5.18%
    PRS 91.39
  • activated CD8-positive, alpha-beta T cell, human CL0001049
    CSI 2.58
    rCSI 4.41%
    PRS 85.57
  • lung resident memory CD8-positive, alpha-beta T cell CL4033039
    CSI 2.56
    rCSI 6.62%
    PRS 90.72
  • innate lymphoid cell CL0001065
    CSI 2.25
    rCSI 4.64%
    PRS 69.7
  • effector memory CD4-positive, alpha-beta T cell CL0000905
    CSI 2.11
    rCSI 2.88%
    PRS 90.64
  • T-helper 17 cell CL0000899
    CSI 2.04
    rCSI 1.62%
    PRS 89.15
  • natural T-regulatory cell CL0000903
    CSI 1.93
    rCSI 3.65%
    PRS 93.04
  • group 2 innate lymphoid cell CL0001069
    CSI 1.65
    rCSI 8.95%
    PRS 92.09
  • CD8-positive, CD28-negative, alpha-beta regulatory T cell CL0000920
    CSI 1.62
    rCSI 3.23%
    PRS 84.97
  • granulocyte CL0000094
    CSI 1.25
    rCSI 1.91%
    PRS 79.23
  • CD8-alpha-alpha-positive, alpha-beta intraepithelial T cell CL0000915
    CSI 1.18
    rCSI 5.38%
    PRS 91.51
  • mature alpha-beta T cell CL0000791
    CSI 1.03
    rCSI 3.73%
    PRS 87.4
  • decidual natural killer cell, human CL0002343
    CSI 0.77
    rCSI 7.83%
    PRS 89.73
  • cytotoxic T cell CL0000910
    CSI 0.55
    rCSI 3.17%
    PRS 77.44
  • helper T cell CL0000912
    CSI 0.51
    rCSI 0.72%
    PRS 72.79
  • double negative T regulatory cell CL0011024
    CSI 0.45
    rCSI 8.54%
    PRS 92.6

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Legend:
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  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [GZMM](/details-gene/3004) (Granzyme M) is a protein-coding gene located on chromosome 19p13.3 that encodes a serine protease. It is a member of the granzyme family, which are key effector molecules in cytotoxic lymphocytes. The primary function of [GZMM](/details-gene/3004) is to induce apoptosis in target cells, playing a critical role in cell-mediated cytotoxicity, particularly within the innate immune system. Its expression is highly enriched in cytotoxic immune cell populations, most notably [natural killer (NK) cells](/details-cell/CL0000939) and various subsets of [T cells](/details-cell/CL0000084), consistent with its function as a mediator of immune surveillance and defense. Early research identified it as a serine protease preferentially expressed in human natural killer cells, then known as Met-ase ([Link](https://pubmed.ncbi.nlm.nih.gov/8245461/)). ## Cellular Roles and Expression Landscape The expression profile of [GZMM](/details-gene/3004) firmly establishes it as a key component of the cytotoxic lymphocyte arsenal. **Overall**, the gene shows the highest significance in cells responsible for direct cell killing and immune regulation. Its most prominent expression is in natural killer cells, with exceptionally high significance in both [CD16-positive, CD56-dim natural killer cell, human](/details-cell/CL0000939) (CSI: 102.60) and [CD16-negative, CD56-bright natural killer cell, human](/details-cell/CL0000938) (CSI: 63.41). This suggests that [GZMM](/details-gene/3004) is a fundamental effector molecule for the cytotoxic activity of both major NK cell subsets. Beyond NK cells, [GZMM](/details-gene/3004) is significantly expressed across a broad spectrum of T cell lineages. It is a strong marker in [central memory CD8-positive, alpha-beta T cell](/details-cell/CL0000907) (CSI: 49.80), indicating a role in long-term cytotoxic memory. Its expression extends to other unconventional T cell types, including [activated type II NK T cell](/details-cell/CL0000931), [gamma-delta T cell](/details-cell/CL0000798), and [mucosal invariant T cell](/details-cell/CL0000940). The notable significance in [naive T cell](/details-cell/CL0000898) and various thymocyte populations, such as [double negative thymocyte](/details-cell/CL0002489), suggests that its expression is initiated early during lymphocyte development and may serve functions beyond immediate effector activity. ## Pathways and Molecular Function Functionally, [GZMM](/details-gene/3004) operates as a serine-type endopeptidase ([GO:0004252](https://www.ebi.ac.uk/QuickGO/term/GO:0004252)), mediating proteolysis ([GO:0006508](https://www.ebi.ac.uk/QuickGO/term/GO:0006508)) to trigger an [apoptotic process](/details-gene/GO:0006915) in target cells. Its involvement in pathways such as [T cell mediated cytotoxicity](/details-gene/GO:0001913) aligns perfectly with its high expression in cytotoxic T lymphocytes. As a component of the [Innate immune system](/details-pathway/R-HSA-168249), it also participates in the broader [Immune system](/details-pathway/R-HSA-168256) response, including potential roles in the [Complement cascade](/details-pathway/R-HSA-166658). Mechanistically, [GZMM](/details-gene/3004) induces cell death through unique substrate cleavage. Research has shown it can target alpha-tubulin, leading to the disorganization of the microtubule network ([Link](https://doi.org/10.4049/jimmunol.180.12.8184)). Another key pathway involves the cleavage of the anti-apoptotic protein survivin, which disrupts the survivin-XIAP complex, thereby liberating caspase activity and promoting cytolysis in tumor cells ([Link](https://doi.org/10.1074/jbc.m109.083170)). These specific actions underscore its role as a potent executioner molecule in the immune system. ## Research Directions The well-defined role of [GZMM](/details-gene/3004) in cytotoxicity, combined with its specific expression pattern, presents several avenues for further investigation and therapeutic exploration. **Proposed Hypotheses:** 1. Given its high expression in both CD56-dim (highly cytotoxic) and CD56-bright (primarily cytokine-producing) NK cells, it is hypothesized that the function or regulation of [GZMM](/details-gene/3004) is context-dependent. In [CD16-positive, CD56-dim natural killer cell, human](/details-cell/CL0000939), it may primarily target substrates for rapid killing, whereas in [CD16-negative, CD56-bright natural killer cell, human](/details-cell/CL0000938), it could cleave substrates involved in modulating the inflammatory microenvironment or influencing target cell immunogenicity. 2. The significant expression of [GZMM](/details-gene/3004) in [naive T cell](/details-cell/CL0000898) populations, which are not terminally differentiated effector cells, suggests a non-cytotoxic, preparatory function. It is hypothesized that low-level [GZMM](/details-gene/3004) activity in naive T cells contributes to cellular homeostasis or primes them for rapid deployment of effector functions upon activation, potentially by regulating the turnover of specific proteins. **Experimental Approach:** To test the first hypothesis regarding the differential function of [GZMM](/details-gene/3004) in NK cell subsets, one could isolate human CD56-dim and CD56-bright NK cells and create [GZMM](/details-gene/3004) knockouts using CRISPR-Cas9. The cytotoxic potential of these knockout cells versus wild-type controls could be assessed against various tumor cell lines. Furthermore, comparative proteomics (e.g., N-terminomics) on target cells treated with purified [GZMM](/details-gene/3004) could identify distinct substrate repertoires, revealing if its targeting priorities differ based on the cellular context from which it is derived. **Therapeutic Potential:** As a key effector molecule in anti-tumor immunity, [GZMM](/details-gene/3004) is a compelling candidate for therapeutic enhancement rather than inhibition. Its activity is central to the efficacy of NK cells and cytotoxic T lymphocytes. Therefore, strategies aimed at augmenting its function could improve cancer immunotherapy. This could involve engineering CAR-T or CAR-NK cells to overexpress [GZMM](/details-gene/3004) or developing small-molecule enhancers that increase its catalytic activity or stability within the tumor microenvironment. Such approaches could potentially overcome tumor-intrinsic resistance mechanisms to apoptosis.

Genular Protein ID: 1504862673

Symbol: GRAM_HUMAN

Name: Granzyme M

UniProtKB Accession Codes:

P51124

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 2 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 CarbonylDB 1 ChEMBL 1 DMDM 1 DNASU 1 DisGeNET 1 EC 1 EMBL 5 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 9 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MEROPS 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 4 PDBsum 4 PIR 1 PRINTS 1 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 2 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 8245461

Title: Met-ase: cloning and distinct chromosomal location of a serine protease preferentially expressed in human natural killer cells.

PubMed ID: 8245461

PubMed ID: 7713495

Title: The human Met-ase gene (GZMM): structure, sequence, and close physical linkage to the serine protease gene cluster on 19p13.3.

PubMed ID: 7713495

DOI: 10.1006/geno.1994.1651

PubMed ID: 15057824

Title: The DNA sequence and biology of human chromosome 19.

PubMed ID: 15057824

DOI: 10.1038/nature02399

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 18523284

Title: NK cell protease granzyme M targets alpha-tubulin and disorganizes the microtubule network.

PubMed ID: 18523284

DOI: 10.4049/jimmunol.180.12.8184

PubMed ID: 20406824

Title: Cleavage of survivin by Granzyme M triggers degradation of the survivin-X-linked inhibitor of apoptosis protein (XIAP) complex to free caspase activity leading to cytolysis of target tumor cells.

PubMed ID: 20406824

DOI: 10.1074/jbc.m109.083170

PubMed ID: 19542453

Title: Structural basis for proteolytic specificity of the human apoptosis-inducing granzyme M.

PubMed ID: 19542453

DOI: 10.4049/jimmunol.0803088

Sequence Information:

  • Length: 257
  • Mass: 27545
  • Checksum: B4E815CE455F7371
  • Sequence:
    • MEACVSSLLV LALGALSVGS SFGTQIIGGR EVIPHSRPYM ASLQRNGSHL CGGVLVHPKW 
VLTAAHCLAQ RMAQLRLVLG LHTLDSPGLT FHIKAAIQHP RYKPVPALEN DLALLQLDGK 
VKPSRTIRPL ALPSKRQVVA AGTRCSMAGW GLTHQGGRLS RVLRELDLQV LDTRMCNNSR 
FWNGSLSPSM VCLAADSKDQ APCKGDSGGP LVCGKGRVLA RVLSFSSRVC TDIFKPPVAT 
AVAPYVSWIR KVTGRSA