Target Information

Target General Information

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Target ID

T18972 (Former ID: TTDNC00504)

Target Name

T-cell surface glycoprotein CD3 gamma (CD3G)

Synonyms

T3G; T-cell surface glycoprotein CD3 gamma chain; T-cell receptor T3 gamma chain; CD3g

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Gene Name

CD3G

Target Type

Clinical trial target

[1]

Disease

[+] 5 Target-related Diseases

Colorectal cancer [ICD-11: 2B91]

Breast cancer [ICD-11: 2C60-2C6Y]

Malignant digestive organ neoplasm [ICD-11: 2C11]

Prostate cancer [ICD-11: 2C82]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Function

When antigen presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of downstream signaling pathways. In addition to this role of signal transduction in T-cell activation, CD3G plays an essential role in the dynamic regulation of TCR expression at the cell surface. Indeed, constitutive TCR cycling is dependent on the di-leucine-based (diL) receptor-sorting motif present in CD3G. Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response.

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UniProt ID

CD3G_HUMAN

Sequence

MEQGKGLAVLILAIILLQGTLAQSIKGNHLVKVYDYQEDGSVLLTCDAEAKNITWFKDGK
MIGFLTEDKKKWNLGSNAKDPRGMYQCKGSQNKSKPLQVYYRMCQNCIELNAATISGFLF
AEIVSIFVLAVGVYFIAGQDGVRQSRASDKQTLLPNDQLYQPLKDREDDQYSHLQGNQLR
RN

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3D Structure

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PDB

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 5 Clinical Trial Drugs

Ertumaxomab

Drug Info

Phase 2

Breast cancer

[2], [3]

MGD007

Drug Info

Phase 1/2

Colorectal cancer

[4]

Autologous T-cell therapy

Drug Info

Phase 1

Prostate cancer

[5]

MEDI-565

Drug Info

Phase 1

Gastrointestinal cancer

[6]

MT-110

Drug Info

Phase 1

Solid tumour/cancer

[7]

Mode of Action

[+] 1 Modes of Action

Modulator

[+] 2 Modulator drugs

MGD007

Drug Info

[8]

MEDI-565

Drug Info

[8]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Hemicentin-2 (HMCN2)	PF12662 ; PF07645 ; PF07474 ; PF07679 ; PF13927 More >>	34.211 (26/76)	1.00E-03


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
Hematopoietic cell lineage	hsa04640	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Th1 and Th2 cell differentiation	hsa04658	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Th17 cell differentiation	hsa04659	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
T cell receptor signaling pathway	hsa04660	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Degree	12	Degree centrality	1.29E-03	Betweenness centrality	2.65E-06
Closeness centrality	2.16E-01	Radiality	1.38E+01	Clustering coefficient	8.48E-01
Neighborhood connectivity	3.35E+01	Topological coefficient	1.95E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 5 KEGG Pathways

Hematopoietic cell lineage

T cell receptor signaling pathway

Chagas disease (American trypanosomiasis)

Measles

HTLV-I infection

NetPath Pathway

[+] 1 NetPath Pathways

TCR Signaling Pathway

Panther Pathway

[+] 1 Panther Pathways

T cell activation

PID Pathway

[+] 8 PID Pathways

TCR signaling in na&#xef

IL12-mediated signaling events

TCR signaling in na&#xef

CXCR4-mediated signaling events

Downstream signaling in na&#xef

IL12 signaling mediated by STAT4

Reactome

[+] 8 Reactome Pathways

Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell

Phosphorylation of CD3 and TCR zeta chains

Translocation of ZAP-70 to Immunological synapse

Generation of second messenger molecules

FCGR activation

Regulation of actin dynamics for phagocytic cup formation

Role of phospholipids in phagocytosis

PD-1 signaling

WikiPathways

[+] 5 WikiPathways

TCR Signaling Pathway

Fcgamma receptor (FCGR) dependent phagocytosis

TCR signaling

Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell

Costimulation by the CD28 family

References

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REF 1

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 2

Trifunctional antibody ertumaxomab: Non-immunological effects on Her2 receptor activity and downstream signaling. MAbs. 2012 Sep-Oct;4(5):614-22.

REF 3

Ertumaxomab: a trifunctional antibody for breast cancer treatment. Expert Opin Investig Drugs. 2008 Oct;17(10):1553-8.

REF 4

ClinicalTrials.gov (NCT03531632) MGD007 Combined With MGA012 in Relapsed/Refractory Metastatic Colorectal Cancer. U.S. National Institutes of Health.

REF 5

Clinical application of genetically modified T cells in cancer therapy. Clin Transl Immunology. 2014 May 16;3(5):e16.

REF 6

ClinicalTrials.gov (NCT01284231) A Study to Evaluate the Safety and Tolerability of MEDI-565 in Adults With Gastrointestinal Adenocarcinomas. U.S. National Institutes of Health.

REF 7

EpCAM/CD3-Bispecific T-cell engaging antibody MT110 eliminates primary human pancreatic cancer stem cells. Clin Cancer Res. 2012 Jan 15;18(2):465-74.

REF 8

Bispecific antibodies rise again. Nat Rev Drug Discov. 2014 Nov;13(11):799-801.

REF 9

Antitumor activities of PSMA CD3 diabodies by redirected T-cell lysis of prostate cancer cells. Immunotherapy. 2013 Jan;5(1):27-38.

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