InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: ABL1

Summary

InnateDB Protein

IDBP-89601.7

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

ABL1

Protein Name

c-abl oncogene 1, non-receptor tyrosine kinase

Synonyms

ABL; bcr/abl; c-ABL; c-ABL1; JTK7; p150; v-abl;

Species

Homo sapiens

Ensembl Protein

ENSP00000361423

InnateDB Gene

IDBG-89599 (ABL1)

Protein Structure

UniProt Annotation

Function

Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage- induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin- associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1. {ECO:0000269PubMed:10391250, ECO:0000269PubMed:11971963, ECO:0000269PubMed:12379650, ECO:0000269PubMed:12531427, ECO:0000269PubMed:12672821, ECO:0000269PubMed:15031292, ECO:0000269PubMed:15556646, ECO:0000269PubMed:15657060, ECO:0000269PubMed:15886098, ECO:0000269PubMed:16424036, ECO:0000269PubMed:16678104, ECO:0000269PubMed:16943190, ECO:0000269PubMed:17306540, ECO:0000269PubMed:17623672, ECO:0000269PubMed:18328268, ECO:0000269PubMed:18945674, ECO:0000269PubMed:19891780, ECO:0000269PubMed:20357770, ECO:0000269PubMed:20417104, ECO:0000269PubMed:9037071, ECO:0000269PubMed:9144171, ECO:0000269PubMed:9461559}.

Subcellular Localization

Cytoplasm, cytoskeleton. Nucleus. Mitochondrion {ECO:0000250}. Note=Shuttles between the nucleus and cytoplasm depending on environmental signals. Sequestered into the cytoplasm through interaction with 14-3-3 proteins. Localizes to mitochondria in response to oxidative stress (By similarity). {ECO:0000250}.Isoform IB: Nucleus membrane; Lipid-anchor. Note=The myristoylated c-ABL protein is reported to be nuclear.

Disease Associations

Leukemia, chronic myeloid (CML) [MIM:608232]: A clonal myeloproliferative disorder of a pluripotent stem cell with a specific cytogenetic abnormality, the Philadelphia chromosome (Ph), involving myeloid, erythroid, megakaryocytic, B-lymphoid, and sometimes T-lymphoid cells, but not marrow fibroblasts. Note=The gene represented in this entry is involved in disease pathogenesis.Note=A chromosomal aberration involving ABL1 has been found in patients with chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

Tissue Specificity

Widely expressed.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 266 experimentally validated interaction(s) in this database.
They are also associated with 29 interaction(s) predicted by orthology.

Experimentally validated
Total	266 [view]
Protein-Protein	264 [view]
Protein-DNA	2 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	29 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0000287	magnesium ion binding
GO:0003677	DNA binding
GO:0003785	actin monomer binding
GO:0004515	nicotinate-nucleotide adenylyltransferase activity
GO:0004672	protein kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0004715	non-membrane spanning protein tyrosine kinase activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0008022	protein C-terminus binding
GO:0016301	kinase activity
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0017124	SH3 domain binding
GO:0019904	protein domain specific binding
GO:0019905	syntaxin binding
GO:0030145	manganese ion binding
GO:0051019	mitogen-activated protein kinase binding
GO:0070064	proline-rich region binding

Biological Process

GO:0006298	mismatch repair
GO:0006355	regulation of transcription, DNA-templated
GO:0006464	cellular protein modification process
GO:0006468	protein phosphorylation
GO:0006914	autophagy
GO:0006974	cellular response to DNA damage stimulus
GO:0006975	DNA damage induced protein phosphorylation
GO:0007155	cell adhesion
GO:0007411	axon guidance
GO:0007596	blood coagulation
GO:0008630	intrinsic apoptotic signaling pathway in response to DNA damage
GO:0010506	regulation of autophagy
GO:0018108	peptidyl-tyrosine phosphorylation
GO:0030036	actin cytoskeleton organization
GO:0030100	regulation of endocytosis
GO:0030155	regulation of cell adhesion
GO:0038096	Fc-gamma receptor signaling pathway involved in phagocytosis
GO:0042692	muscle cell differentiation
GO:0042770	signal transduction in response to DNA damage
GO:0043065	positive regulation of apoptotic process
GO:0045087	innate immune response (InnateDB)
GO:0048008	platelet-derived growth factor receptor signaling pathway
GO:0050731	positive regulation of peptidyl-tyrosine phosphorylation
GO:0051149	positive regulation of muscle cell differentiation
GO:0051353	positive regulation of oxidoreductase activity
GO:0051726	regulation of cell cycle
GO:0071901	negative regulation of protein serine/threonine kinase activity
GO:2000145	regulation of cell motility
GO:2000249	regulation of actin cytoskeleton reorganization
GO:2001020	regulation of response to DNA damage stimulus

Cellular Component

GO:0005634	nucleus
GO:0005730	nucleolus
GO:0005737	cytoplasm
GO:0005739	mitochondrion
GO:0005829	cytosol
GO:0015629	actin cytoskeleton
GO:0031252	cell leading edge
GO:0031965	nuclear membrane
GO:0048471	perinuclear region of cytoplasm

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR000980 SH2 domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR001452 SH3 domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR011009 Protein kinase-like domain
IPR011511 Variant SH3 domain
IPR015015 F-actin binding
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM