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FLASH GENE

Symbol

AGR2

contributors: mct - updated : 11-01-2012

HGNC name	anterior gradient 2 homolog (Xenopus laevis)
HGNC id	328

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	12.47 kb     8 Exon(s)

10 Kb 5' upstream gene genomic sequence study

motif

repetitive sequence   ALU   long interspersed repetitive elements

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_006408 8 - 996 19 175 - 2005 15834940 AGR2S AGR2L - - 1701 19 175 - 2005 15834940

EXPRESSION

Type

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine large intestine colon   highly Homo sapiens   stomach       highly Endocrine pancreas       highly Reproductive female system breast mammary gland       male system prostate

cells

System Cell Pubmed Species Stage Rna symbol not specific epithelial cell

cell lineage
cell lines	estrogen receptor-positive breast cancer cell lines
fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N terminus contains a sequence motif characteristic of signal peptides, which results in protein targeting to the secretory pathway of the cell
	a thioredoxin-like motif
	C-terminal ER retention motif (KTEL) , variations in ER localization sequences may serve a specific functional role, and this role is served specifically by KTEL

mono polymer

homomer , dimer

HOMOLOGY

interspecies	ortholog to murine Agr2
	homolog to xenopus xag2

intraspecies

homolog to ERP29, TXNDC12

Homologene

FAMILY

disulfide isomerase family

CATEGORY

secretory , protooncogene , signaling

SUBCELLULAR LOCALIZATION	extracellular
	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,cytoplasm,organelle,lumen
	intracellular,cytoplasm,organelle,endoplasmic reticulum
text	localizes to the lumen of the ER and indirectly associates with ER membrane-bound ribosomes through nascent protein chains

basic FUNCTION	putative signaling molecule involved in cell differentiation and/or in secretory functions of the prostate gland
	unique member of the PDI family, with a specialized and nonredundant role in intestinal mucus production
	estrogen-responsive secreted protein
	functions in a range of biological systems, including goblet cell formation, limb regeneration, inhibition of TP53, and metastasis (
	induces expression of amphiregulin (AREG), a growth promoting EGFR ligand
	may function in a non-cell autonomous fashion
	promotes growth by regulating the Hippo and EGF receptor signaling pathways
	induces AREG expression through YAP1
	promotes dissemination of pancreatic cancer and its cell surface targeting may permit new strategies for early detection as well as therapeutic management
	extracellular role for AGR2 as a secreted protein as well as an intracellular role as a protein chaperone or stress response factor
	pro-oncogenic and may thus represent a mechanistic intermediate in the connection between ERAD, ERQC and cancer development
	might play an essential role for in vivo production of the intestinal mucus protein mucin 2 (MUC2), a large cysteine-rich glycoprotein
	by regulating the ER capacity to adapt, might have an impact on cell survival, consequently contributing to the development and progression of cancers
	promotes tumor growth and metastasis
	its localization in the ER by KTEL is required for its ability to induce AREG or CDX2 expression
	dimerization of AGR2 is critical step to modulate UPR signaling pathway

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

homo-dimerizes through an intermolecular disulfide bond

INTERACTION

DNA

RNA

small molecule

protein	estrogen receptor
	RUVBL2 is an AGR2-interacting protein
	regulates AREG RNA and protein expression
	interacting with CTSB, CTSD (promotes the dissemination of pancreatic cancer cells through regulation of cathepsins IRE1B and D)
	expression is under the control of both ATF6 and ERN1 arms of the UPR, which might suggest tight maintenance of AGR2 levels in the cell
	dimerization of AGR2 attenuates ER stress-induced cell death through the association with HSPA5

cell & other

REGULATION

induced by

various stresses such as hypoxia, serum depletion, and ER stress

Other

regulated by androgens

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in early stage mucinous ovarian tumors compared to normal ovarian tissues and serous type ovarian tumors tumoral     --over   in prostate cancer compared to non-malignant cells, but relatively lower levels of AGR2 are highly predictive of disease recurrence following radical prostatectomy tumoral     --over   in breast cancer

Susceptibility

to ulcerative colitis

Variant & Polymorphism

Candidate gene
Marker	potential biomarker for the diagnosis of mucinous ovarian cancer
Therapy target
	System Type Disorder Pubmed cancer reproductive breast utility of anti-AGR2 therapy in ER-positive breast cancers because of its impact on cancer-relevant pathways cancer digestive pancreas may be a useful molecular target in pancreatic cancer

ANIMAL & CELL MODELS

mice lacking Agr2 were viable but were highly susceptible to colitis, indicating a critical role for Agr2 in protection from disease