TISIDB

Summary
Symbol	ARG1
Name	arginase 1
Aliases	arginase, liver; liver-type arginase; type I arginase; Arginase-1
Chromosomal Location	6q23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Cytoplasm Cytoplasmic granule Note=Localized in azurophil granules of neutrophils (PubMed:15546957).
Domain	PF00491 Arginase family
Function	Key element of the urea cycle converting L-arginine to urea and L-ornithine, which is further metabolized into metabolites proline and polyamides that drive collagen synthesis and bioenergetic pathways critical for cell proliferation, respectively; the urea cycle takes place primarily in the liver and, to a lesser extent, in the kidneys. ; FUNCTION: Functions in L-arginine homeostasis in nonhepatic tissues characterized by the competition between nitric oxide synthase (NOS) and arginase for the available intracellular substrate arginine. Arginine metabolism is a critical regulator of innate and adaptive immune responses. Involved in an antimicrobial effector pathway in polymorphonuclear granulocytes (PMN). Upon PMN cell death is liberated from the phagolysosome and depletes arginine in the microenvironment leading to suppressed T cell and natural killer (NK) cell proliferation and cytokine secretion (PubMed:15546957, PubMed:16709924, PubMed:19380772). In group 2 innate lymphoid cells (ILC2s) promotes acute type 2 inflammation in the lung and is involved in optimal ILC2 proliferation but not survival (By similarity). In humans, the immunological role in the monocytic/macrophage/dendritic cell (DC) lineage is unsure.

> Gene Ontology [ TOP ]
Biological Process	GO:0000050 urea cycle GO:0000302 response to reactive oxygen species GO:0001101 response to acid chemical GO:0001889 liver development GO:0001935 endothelial cell proliferation GO:0001936 regulation of endothelial cell proliferation GO:0001938 positive regulation of endothelial cell proliferation GO:0002237 response to molecule of bacterial origin GO:0006520 cellular amino acid metabolic process GO:0006525 arginine metabolic process GO:0006527 arginine catabolic process GO:0006591 ornithine metabolic process GO:0006865 amino acid transport GO:0006979 response to oxidative stress GO:0007565 female pregnancy GO:0007568 aging GO:0007584 response to nutrient GO:0009063 cellular amino acid catabolic process GO:0009064 glutamine family amino acid metabolic process GO:0009065 glutamine family amino acid catabolic process GO:0009635 response to herbicide GO:0009636 response to toxic substance GO:0009991 response to extracellular stimulus GO:0010035 response to inorganic substance GO:0010038 response to metal ion GO:0010042 response to manganese ion GO:0010043 response to zinc ion GO:0010269 response to selenium ion GO:0010958 regulation of amino acid import GO:0010963 regulation of L-arginine import GO:0014075 response to amine GO:0015837 amine transport GO:0015849 organic acid transport GO:0016054 organic acid catabolic process GO:0019547 arginine catabolic process to ornithine GO:0019627 urea metabolic process GO:0022612 gland morphogenesis GO:0030323 respiratory tube development GO:0030324 lung development GO:0030879 mammary gland development GO:0031667 response to nutrient levels GO:0031960 response to corticosteroid GO:0032496 response to lipopolysaccharide GO:0032890 regulation of organic acid transport GO:0032963 collagen metabolic process GO:0032964 collagen biosynthetic process GO:0033189 response to vitamin A GO:0033197 response to vitamin E GO:0033273 response to vitamin GO:0033762 response to glucagon GO:0034599 cellular response to oxidative stress GO:0034614 cellular response to reactive oxygen species GO:0042493 response to drug GO:0042542 response to hydrogen peroxide GO:0043090 amino acid import GO:0043091 L-arginine import GO:0043092 L-amino acid import GO:0043200 response to amino acid GO:0043434 response to peptide hormone GO:0044236 multicellular organism metabolic process GO:0044259 multicellular organismal macromolecule metabolic process GO:0044282 small molecule catabolic process GO:0044706 multi-multicellular organism process GO:0046395 carboxylic acid catabolic process GO:0046686 response to cadmium ion GO:0048545 response to steroid hormone GO:0048678 response to axon injury GO:0048732 gland development GO:0048771 tissue remodeling GO:0050673 epithelial cell proliferation GO:0050678 regulation of epithelial cell proliferation GO:0050679 positive regulation of epithelial cell proliferation GO:0051259 protein oligomerization GO:0051260 protein homooligomerization GO:0051384 response to glucocorticoid GO:0051597 response to methylmercury GO:0051952 regulation of amine transport GO:0051955 regulation of amino acid transport GO:0060056 mammary gland involution GO:0060135 maternal process involved in female pregnancy GO:0060443 mammary gland morphogenesis GO:0060541 respiratory system development GO:0061008 hepaticobiliary system development GO:0070206 protein trimerization GO:0070207 protein homotrimerization GO:0070301 cellular response to hydrogen peroxide GO:0070670 response to interleukin-4 GO:0071216 cellular response to biotic stimulus GO:0071219 cellular response to molecule of bacterial origin GO:0071222 cellular response to lipopolysaccharide GO:0071353 cellular response to interleukin-4 GO:0071375 cellular response to peptide hormone stimulus GO:0071377 cellular response to glucagon stimulus GO:0071383 cellular response to steroid hormone stimulus GO:0071384 cellular response to corticosteroid stimulus GO:0071385 cellular response to glucocorticoid stimulus GO:0071396 cellular response to lipid GO:0071407 cellular response to organic cyclic compound GO:0071417 cellular response to organonitrogen compound GO:0071548 response to dexamethasone GO:0071549 cellular response to dexamethasone stimulus GO:0071559 response to transforming growth factor beta GO:0071560 cellular response to transforming growth factor beta stimulus GO:0071941 nitrogen cycle metabolic process GO:0090467 arginine import GO:1901565 organonitrogen compound catabolic process GO:1901605 alpha-amino acid metabolic process GO:1901606 alpha-amino acid catabolic process GO:1901652 response to peptide GO:1901653 cellular response to peptide GO:1901654 response to ketone GO:1901655 cellular response to ketone GO:1902023 L-arginine transport GO:1990267 response to transition metal nanoparticle
Molecular Function	GO:0004053 arginase activity GO:0016810 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds GO:0016813 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amidines GO:0030145 manganese ion binding
Cellular Component	GO:0005741 mitochondrial outer membrane GO:0019867 outer membrane GO:0031968 organelle outer membrane GO:0043025 neuronal cell body GO:0044297 cell body

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa00330 Arginine and proline metabolism hsa01100 Metabolic pathways hsa01230 Biosynthesis of amino acids
Reactome	R-HSA-168256: Immune System R-HSA-168249: Innate Immune System R-HSA-1430728: Metabolism R-HSA-71291: Metabolism of amino acids and derivatives R-HSA-351202: Metabolism of polyamines R-HSA-6798695: Neutrophil degranulation R-HSA-70635: Urea cycle

Summary
Symbol	ARG1
Name	arginase 1
Aliases	arginase, liver; liver-type arginase; type I arginase; Arginase-1
Chromosomal Location	6q23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between ARG1 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between ARG1 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
26740106	Head and Neck Squamous Cell Carcinoma	Inhibit immunity (T cell function)	Similarly, knockdown of Sema4D in an HNSCC cell line resulted in a loss of MDSC function as shown by a decrease in the production of the immune-suppressive cytokines arginase-1, TGF-β, and IL-10 by MDSC, concomitant with recovery of T cell proliferation and IFN-γ production following stimulation of CD3/CD28.
25967142	Prostate Carcinoma	Inhibit immunity (T cell function)	TLR9-Targeted STAT3 Silencing Abrogates Immunosuppressive Activity of Myeloid-Derived Suppressor Cells from Prostate Cancer Patients. These effects depended on reduced expression and enzymatic activity of Arginase-1, a downstream STAT3 target gene and a potent T cell inhibitor.
22474024	Colon Carcinoma	Inhibit immunity (T cell function)	Experiments using small interfering RNA and a chemical inhibitor of FKBP51 revealed that FKBP51 contributes to the regulation of the suppressive function of MDSCs by increasing inducible NO synthase, arginase-1, and reactive oxygen species levels and enhancing NF-κB activity.
19431148	Non-small-cell lung carcinoma	Inhibit immunity (T cell function)	Arginase 1 (ARG1) inhibits T-cell proliferation by degrading extracellular arginine, which results in decreased responsiveness of T cells to CD3/TCR stimulation.
23420584	Malignant Splenic Neoplasm	Inhibit immunity (T cell function)	Here, we show that lactic acid, or more specifically the acidification it causes, increases arginase I (ARG1) expression in macrophages to inhibit T-cell proliferation and activation. We show that dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinases, targets macrophages to suppress activation of the IL-23/IL-17 pathway and the expression of ARG1 by lactic acid. DCA treatment decreased ARG1 expression in tumor-infiltrating immune cells and increased the number of IFN-γ-producing CD8+ T cells and NK cells in tumor-bearing mouse spleen.
29034589	Colon Carcinoma	Inhibit immunity (T cell function)	Giving angiotensin II receptor blockers (ARB) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b+ myeloid cells in tumors, but significantly reduced their T-cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)-6, IL-10, vascular endothelial growth factor (VEGF), and arginase by CD11b+ cells in tumors.
23665041	Hepatocellular Carcinoma	Inhibit immunity (T cell function)	Such CD14(+)HLA-DR(-/low) monocyte-derived MDSCs suppressed T-cell proliferation in an arginase-1 dependent fashion. HSC-induced development of CD14(+)HLA-DR(-/low) monocyte-derived MDSCs was not mediated by soluble factors, but required physical interaction and was abrogated by blocking CD44. Thus, our data suggest that local generation of MDSCs by liver-resident HSCs may contribute to immune suppression during inflammation and cancer in the liver.
29124314	Melanoma	Inhibit immunity	Furthermore, Foxp3 vaccination resulted in a significant reduction of arginase-1(Arg-1)-induced nitric oxide synthase (iNOS), reactive oxygen species (ROS) and suppressed MDSC activity.
25084511	Cervical Carcinoma	Inhibit immunity	This study indicates that ASE activity and L-Arg degradation mechanisms of immunosuppression are present in cervical cancer.
21948231	glioblastoma	Inhibit immunity	These data indicate that peripheral cellular immunosuppression in patients with GBM is associated with neutrophil degranulation and elevated levels of circulating ArgI, and that T-cell function can be restored in these individuals by targeting ArgI.

Summary
Symbol	ARG1
Name	arginase 1
Aliases	arginase, liver; liver-type arginase; type I arginase; Arginase-1
Chromosomal Location	6q23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of ARG1 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	ARG1
Name	arginase 1
Aliases	arginase, liver; liver-type arginase; type I arginase; Arginase-1
Chromosomal Location	6q23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of ARG1 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	1.119	0.188
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.165	0.903
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	2.078	0.0687
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.296	0.676
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.795	0.55
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.322	0.819
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.127	0.903
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.793	0.61
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.795	0.614
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.156	0.912
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	0.563	0.76
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.803	0.0171

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of ARG1 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	3.7	1.4	2.3	0.469
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	3.7	1.7	2	0.532
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	5.9	-5.9	0.447
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	9.1	-9.1	0.458
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	11.1	0	11.1	0.36
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	25	0	25	0.364
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	0	0	0	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	ARG1
Name	arginase 1
Aliases	arginase, liver; liver-type arginase; type I arginase; Arginase-1
Chromosomal Location	6q23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of ARG1. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	ARG1
Name	arginase 1
Aliases	arginase, liver; liver-type arginase; type I arginase; Arginase-1
Chromosomal Location	6q23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of ARG1. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by ARG1. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	ARG1
Name	arginase 1
Aliases	arginase, liver; liver-type arginase; type I arginase; Arginase-1
Chromosomal Location	6q23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of ARG1. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	ARG1
Name	arginase 1
Aliases	arginase, liver; liver-type arginase; type I arginase; Arginase-1
Chromosomal Location	6q23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of ARG1 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	ARG1
Name	arginase 1
Aliases	arginase, liver; liver-type arginase; type I arginase; Arginase-1
Chromosomal Location	6q23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between ARG1 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	ARG1
Name	arginase 1
Aliases	arginase, liver; liver-type arginase; type I arginase; Arginase-1
Chromosomal Location	6q23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting ARG1 collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting ARG1.

ID	Name	Drug Type	Targets	#Targets
DB00129	Ornithine	Small Molecule	ARG1, ARG2, GATM, OAT, OAZ1, OAZ2, OAZ3, OTC, SLC25A15, SLC25A2, S ......	14
DB01983	2(S)-Amino-6-Boronohexanoic Acid	Small Molecule	ARG1	1
DB02381	nor-NOHA	Small Molecule	ARG1	1
DB02499	Dinor-N(Omega)-Hydroxy-L-Arginine	Small Molecule	ARG1	1
DB02689	S-{2-[Amino(Dihydroxy)-Lambda~4~-Sulfanyl]Ethyl}-D-Cysteine	Small Molecule	ARG1	1
DB03144	N-Omega-Hydroxy-L-Arginine	Small Molecule	ARG1, NOS1, NOS2, NOS3	4
DB03731	S-2-(Boronoethyl)-L-Cysteine	Small Molecule	ARG1, ARG2	2
DB03904	Urea	Small Molecule	ARG1, CA2, CTNNB1	3
DB04197	Descarboxy-nor-N(Omega)-Hydroxy-L-Arginine	Small Molecule	ARG1	1
DB04530	S,S-(2-Hydroxyethyl)Thiocysteine	Small Molecule	ARG1, CYTH2, PDE1B, PDE4B, PIM1, PRKACA, SERPINB5, SNX3, TYMS	9
DB04585	DEHYDRO-2(S)-AMINO-6-BORONOHEXANOIC ACID	Small Molecule	ARG1	1
DB04648	S-propylamine-L-cysteine	Small Molecule	ARG1	1
DB06757	Manganese	Small Molecule	ARG1, IDH3A, IDH3G, TAB1, TF	5

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