ATG2B (Autophagy-related 2B)

2016-10-01 Christine Bellanné-Chantelot , Isabelle Plo Affiliation

Identity

HGNC

ATG2B

LOCATION

14q32.2

LOCUSID

55102

ALIAS

C14orf103

FUSION GENES

Show Gene Fusions

Abstract

Autophagy is a cellular process involved in the sequestration of cytosolic components and their degradation by lysosomes. Autophagy has been involved in physiological responses to stress or aging and in the development of many human diseases including solid and haematological cancers. In humans, 16 autophagy-related genes are known. The ATG2B protein is involved in the late steps of the autophagy process i.e. the formation of autophagosomes that fuse with lysosomes before degradation. Loss-of -function (frameshift) acquired mutations of ATG2B have been identified in gastric and colorectal carcinomas with high microsatellite instability. Both pharmacologic and genetic evidence indicate that autophagy plays pleiotropic functions in hematopoietic cell homeostasis and leukemogeneis. Autophagy could exert two opposite roles (cell death and survival) depending on the nature of the hematopoietic malignancy.

DNA/RNA

Description

The ATG2B gene consists of 42 exons spanning a region of 82.08 kb.

Transcription

A single mRNA transcript (NM_018036.6) of the ATG2B gene, with a total length of 6234 nucleotides, has been annotated.

Pseudogene

Not yet identified.

Proteins

Description

The protein encoded by the ATG2B gene is the autophagy-related protein 2 homolog B of 2078 amino acids, with a calculated molecular mass of 232.8 kDa

Expression

Expression of ATG2B has been detected in various normal human tissues (bone marrow, whole blood, thymus, brain, heart, muscle, colon, kidney, liver, lung, pancreas, thyroid, salivary and adrenal glands, skin, ovary, uterus, placenta, prostate and testis).
In hematopoietic cells, ATG2B is expressed in CD34⁺ purified hematopoietic progenitors and CD36⁺ erythroblasts or CD41⁺ megakaryocytes derived from CD34⁺ progenitors cultured in vitro (Saliba et al, 2016)

Localisation

ATG2B is mainly localized in the nucleus.

Function

Autophagy is an intracellular degradation system by which cytoplasmic materials are enclosed by the autophagosomes and transferred to lysosomes before degradation. The autophagy process has been extensively studied in yeast; 35 autophagy-related genes (ATG) have been identified, of which 16 are currently known in humans . This cellular process is a highly conserved among species. In humans, two ATG2 proteins, ATG2A and ATG2B, have redundant functions and are required for autophagosome formation (Velikkakath AK et al , 2012).

Homology

44.5% of human ATG2B residues are identical to those of human ATG2A.

Mutations

Germinal

A germline 14q32.2 head-to-tail duplication of 700 kb has been associated with familial myeloid malignancies (Saliba et al , 2015). The germline duplication includes the genes TCL1A, GSKIP, ATG2B, BDKRB1, BDKRB2 and the first exon of AK7. The overexpression of ATG2B and GSKIP that are expressed in myeloid cells, enhances hematopoietic progenitor differentiation, particularly of megacaryocytes. The development of myeloid malignancies required the cooperation of both genes with the myeloproliferative neoplasms (MPN) driver JAK2^Val617Phe mutation, MPL or CALR mutations. The mechanism of cooperation between ATG2B and GSKIP with MPN driver mutations remains unknown.
The germline duplication with the same distal and proximal breakpoints has only been identified in MPN families originated from West Indies (Martinique) suggesting a founder effect.

Somatic

A loss-of-function somatic mutation (c.3120delA, p.Lys1040fs) in gastric carcinomas (15.6%) and in colorectal carcinomas (11.6%) (Klionsky DJ, 2009).

Implicated in

Entity name

Familial myeloproliferative neoplasms (MPN)

Disease

Familial MPN, in particular, essential thrombocythemia progressing to myelofibrosis and/or acute myeloid leukemia and primary myelofibrosis, with autosomal dominant inheritance and originated from West-indies (Martinique) may be linked to ATG2B/GSKIP germline duplication. The predisposition is highly penetrant (80%) and is characterized by an earlier age of MPN onset in comparison to sporadic cases (41 years versus > 60 years). The spectrum of acquired driver mutations (JAK2^Val617Phe, MPL and CALR mutations) is similar to the spectrum of mutations in sporadic MPN cases.

Prognosis

The percentage of transformation is close to 50% in these familial MPN cases and is related to the detection of mutations affecting epigenetic regulator genes such as TET2 IDH1 or IDH2.

Entity name

Acute myeloid leukemia (AML)

Disease

AML originated from West-indies (Martinique) may be linked to ATG2B/GSKIP germline duplication.

Prognosis

The prognosis of the disease is also linked to the detection of acquired mutations in TET2, IDH1 or in IDH2. No TP53 mutation was found, contrary to what was observed in AML evolving from MPN, suggesting a different pathway for leukemic transformation.

Entity name

Gastric carcinoma

Note

Loss-of-functions somatic mutations in ATG genes (ATG2B, ATG5, ATG9B and ATG12) are identified in 28% of gastric carcinomas with high microsatellite instability. These mutations may contribute to cancer development by deregulating the autophagy process (Kang et al, 2009).

Entity name

Colorectal cancer

Note

Loss-of-functions somatic mutations in ATG genes (ATG2B, ATG5, ATG9B and ATG12) are identified in 28% of colorectal carcinomas with high microsatellite instability. These mutations may contribute to cancer development by deregulating the autophagy process (Kang et al, 2009).

Article Bibliography

Pubmed ID	Last Year	Title	Authors
19197948	2009	Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability.	Kang MR et al
17712358	2007	Autophagy: from phenomenology to molecular understanding in less than a decade.	Klionsky DJ et al
26280900	2015	Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.	Saliba J et al
22219374	2012	Mammalian Atg2 proteins are essential for autophagosome formation and important for regulation of size and distribution of lipid droplets.	Velikkakath AK et al

Other Information

Locus ID:

NCBI: 55102
MIM: 616226
HGNC: 20187
Ensembl: ENSG00000066739

Variants:

dbSNP: 55102
ClinVar: 55102
TCGA: ENSG00000066739
COSMIC: ATG2B

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000066739	ENST00000359933	Q96BY7

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Autophagy - animal	KEGG	ko04140
Autophagy - animal	KEGG	hsa04140
Autophagy - other	KEGG	ko04136
Autophagy - other	KEGG	hsa04136

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
38866787	2024	Human gastric cancer progression and stabilization of ATG2B through RNF5 binding facilitated by autophagy-associated CircDHX8.	0
38866787	2024	Human gastric cancer progression and stabilization of ATG2B through RNF5 binding facilitated by autophagy-associated CircDHX8.	0
34172895	2022	Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms.	8
34748402	2022	Loss of Atg2b and Gskip Impairs the Maintenance of the Hematopoietic Stem Cell Pool Size.	2
35902797	2022	The prognostic value of autophagy related genes with potential protective function in Ewing sarcoma.	4
34172895	2022	Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms.	8
34748402	2022	Loss of Atg2b and Gskip Impairs the Maintenance of the Hematopoietic Stem Cell Pool Size.	2
35902797	2022	The prognostic value of autophagy related genes with potential protective function in Ewing sarcoma.	4
33250346	2021	Polymorphism in autophagy gene ATG2B is not associated with bladder cancer recurrence after intravesical Bacillus Calmette-Guerin (BCG) immunotherapy in Asian patients.	0
33554699	2021	ATG2B/GSKIP in de novo acute myeloid leukemia (AML): high prevalence of germline predisposition in French West Indies.	2
33760149	2021	miR‑143‑3p inhibits endometriotic stromal cell proliferation and invasion by inactivating autophagy in endometriosis.	13
33824300	2021	LncRNA-HOTAIR activates autophagy and promotes the imatinib resistance of gastrointestinal stromal tumor cells through a mechanism involving the miR-130a/ATG2B pathway.	25
34320900	2021	Crocin exerts anti-proliferative and apoptotic effects on cutaneous squamous cell carcinoma via miR-320a/ATG2B.	9
34695177	2021	Downregulation of LINC01296 suppresses non-small-cell lung cancer via targeting miR-143-3p/ATG2B.	6
33250346	2021	Polymorphism in autophagy gene ATG2B is not associated with bladder cancer recurrence after intravesical Bacillus Calmette-Guerin (BCG) immunotherapy in Asian patients.	0

Citation

Christine Bellanné-Chantelot ; Isabelle Plo

ATG2B (Autophagy-related 2B)

Atlas Genet Cytogenet Oncol Haematol. 2016-10-01

Online version: http://atlasgeneticsoncology.org/gene/55326/atg2b-(autophagy-related-2b)