Abl

The Abl family of non-receptor linked tyrosine kinases relay signals from diverse stimuli to promote changes in cell morphogenesis, migration, adhesion, proliferation and survival. Two Abl family kinases are found in vertebrates: Abl and the Abl-related gene (Arg, also known as Abl2) and homologs in metazoan organisms including Drosophila- (D-) Abl and ABL-1 in C. elegans. The N-terminus of mammalian Abl and Arg proteins is variable, encoded by alternative 5’-exons. The variable region is followed by Src homology 3 (SH3), SH2 and tyrosine kinase domains that are highly conserved through evolution. The Abl family kinases are distinguished from the Src-family kinases by their large C-terminal extensions that contain multiple functional domains to mediate interactions with the actin and microtubule cytoskeletons and other cellular components. The mammalian Abl protein contains three nuclear localization signals and one nuclear export signal. Abl has been shown to undergo nucleocytoplasmic shuttling in mammalian cells; its subcellular localization can be modulated by cell adhesion. The Arg and D-Abl proteins are primarily cytoplasmic, consistent with a role for these proteins in regulating cytoskeleton structure.

In the inactive state, the SH3 and SH2 domains of Abl family kinases form an inhibitory scaffold that holds the kinase domain in an inactive conformation. Several cellular proteins, including F-actin and retinoblastoma protein in the nucleus, have been reported to inhibit Abl kinase activity, possibly by stabilizing this inactive conformation. The kinases become activated by the disassembly of the SH3 and SH2 domains from their inhibitory lock on the kinase, possibly by association with higher affinity ligands on activated receptor complexes. Full kinase activation also requires phosphorylation at two or more tyrosine residues in the short linker between the SH2 and kinase domains and in the kinase domain activation loop. Tyrosine phosphorylation of Abl can be catalyzed by autophosphorylation or by Src family kinases. Abl family kinases can be activated by growth factor stimulation, adhesion receptor engagement, DNA damage and under conditions of oxidative stress. Both Src family kinases and phospholipase C g1 have been shown to mediate Abl and Arg activation following growth factor stimulation, but it remains largely unclear how most stimuli activate Abl and Arg kinase activity.

Abl family kinases regulate cell morphology and motility by regulating cytoskeleton dynamics. Abl and Arg also act downstream of adhesion receptors to promote filopodial and lamellipodial dynamics and inhibit cell spreading and cell migration in cultured fibroblasts. Upon growth factor stimulation, Abl promotes membrane ruffling and attenuates chemotaxis. Abl family kinases can promote cytoskeletal rearrangements by phosphorylating the Crk and Dok1 adaptor proteins and the RhoA inhibitor p190RhoGAP. Arg can also promote cytoskeletal rearrangement independent of kinase activity by using its F-actin- and microtubule-binding domains to promote F-actin-rich protrusions at the cell periphery. Genetic studies in mice and flies have suggested that Abl family kinases are important regulators of neuronal and epithelial morphogenesis during development.

Although Abl and Arg can both function in the cytoplasm, the mammalian Abl performs a unique role in the nucleus. Nuclear Abl kinase is activated in response to DNA damage via pathways that depend on ATM and DNA-PK. Activation of nuclear Abl kinase contributes to the growth arrest or apoptotic response to DNA damage, and Abl has been linked to the regulation of p53 and p73, which are related transcription factors with anti-proliferative and pro-apoptotic functions.

Mutational activation of Abl kinase activity causes greater than 95% of human chronic myelogenous leukemia (CML) and a small percentage of cases of acute lymphocytic leukemia, acute myeloid leukemia and chronic neutrophilic leukemia. Oncogenic activation results from translocation between chromosomes 9 and 22 that fuses exons of the Bcr gene to exons of Abl, resulting in a hybrid gene encoding a Bcr-Abl fusion oncoprotein. Bcr-Abl has hyperactive kinase activity and upregulates mitogenic and anti-apoptotic pathways. A selective Abl inhibitor, Imatinib (STI571;Gleevec), has proven effective in the treatment of chronic phase CML patients. CML patients in acute phase or blast crisis, however, develop resistance to imatinib at a high rate, thereby rendering the drug ineffective.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Family Members Abl Arg Bcr-Abl D-Abl Abl-1
Other Names c-Abl
Abl1
JTK7
P150
Abelson nonreceptor tyrosine kinase
Abl2
Ab11
Abelson murine leukemia viral oncogene 2
Abl-related gene
p210
Breakpoint cluster region
Abelson oncogene
Abl-1 Abl
Molecular Weight
123 kDa 124 kDa 210
190
230 kDa
171 kDa 138 kDa
Structural Data 1130 aa 1182 aa   1620 aa 1224 aa
Isoforms Not Known Not Known
Not Known
Not Known
Not Known
Species Mouse
Human
Other vertebrates
Mouse
Human
Other vertebrates
Human
Mouse
Rat
Drosophila melanogaster Caenorhabditis elegans
Domain
Organization
1 SH2 domain
1 SH3 domain
SH1 domain
SH2 domain
SH3 domain
proline-rich
C-term
N-terminal serine/ threonine kinase domain
PH domain
SH2 domain
SH3 domain
SH2 domain
SH3 domain
SH2 domain
SH3 domain
Phosphorylation
Sites
Tyr185
Tyr253
Tyr257
Tyr264
Tyr393
Thr394
Tyr469
Tyr310
Tyr439
Thr440
Tyr515
Tyr177
Tyr328
Ser354
Tyr360
Tyr522 Not Known
Tissue
Distribution
Widely expressed Widely expressed; most abundant in brain and lymphocytes, thymus Myeloid precusor cells, hematopoietic cells CNS, epithelium Not Known
Subcellular
Localization
Nucleus and cytoplasm, focal membrane adhesions, actin cytoskeleton Cytoplasm, lamellipodial protrusions Cytoplasm, F-actin stress fibers Cytoplasm Not Known
Binding Partners/
Associated Proteins
Ab1
crk-II
EVL
IK3-2
Cables
Sema6 D
MYR
p16
DOK1
ABL2
p17
Abi1
Mena
Not Known
GAP
PLCγ1
Src
ARG
c-Abl
p210
Grb2
SOS1
Syp
p160 Bcr
Not Known
Not Known
Upstream
Activators
PDGF receptor
T cell receptor
Src family kinases
Integrin α5β1
PDGF or EGF stimulation
Integrin-mediated adhesion
Genotoxic stress
Ionizing radiation
Oxidative stress
PDGF receptor
T cell receptor
Src family kinases
Integrin α5β1
PDGF or EGF stimulation
Integrin-mediated adhesion
Genotoxic stress
Ionizing radiation
Chromosal translocation creates oncogenic fusion protein, which is constitutively active Dlar
Robo
DE-cadherin
Growth factors
Radiation
Downstream
Activation
Crk
Abi2
Actin
ATM
CD19
p73
Pag
Cables
ABL2
c-Crk
Siva-1
EphB2
PI3K
STAT1
STAT5
STAT6
Ras
PKC
IL-3 paxillin
Vinculin
Actin
Fak
c-Abl
Src
Bcl-2
Neural axon guidance receptors
Fra
Trio
Ena
Clk-2
hus-1
mrt-2
CCP-1
In Vitro Substrates Crk
RNA polymerase II C-terminal domain (CTD)
Various peptides
Shd
p190RhoGAP
Crk
Various peptides
p190RhoGAP
Crk
Various peptides
Not Known
Not Known
In Vivo Substrates Crk
Paxillin
Dok1
Dok2
Crk
p190RhoGAP
Crk
CrkL
Paxillin
Rin1
Jak2
Not Known
Not Known
Activators Not Known
Not Known
Not Known
Not Known
Not Known
Inhibitors Imatinib (Gleevec®)
PD180970 (PZ0142)
PD166325
PD173955
Imatinib (Gleevec®)
PD180970 (PZ0142)
PD166325
Imatinib (Gleevec®)
PD180970
PD166325
PD173955
AG 568
AG 1112 (T6193)
Not Known
Not Known
Selective
Activators
Not Known
Not Known
Not Known
Not Known
Not Known
Physiological
Function
Regulates lymphocyte and osteoblast development, neuronal morphogenesis, neural tube formation Regulates lymphocyte and osteoblast development, neuronal morphogenesis, tube formation
regulates cytoskeleton
Not Known
Regulates neuronal and epithelial morphogenesis Provides protection to ionizing radiation
Disease
Relevance
Chronic myeloid leukemia (CML) Activated by chromosomal translocation in rare cases of acute myeloid leukemia, colon carcinoma, metastatic colon tumors Causes chronic myelogenous and neutrophilic leukemia, acute lymphocytic leukemia, Philadelphia chromosome (Ph1)-positive acute
lymphocytic leukemia
Not Known
Not Known

 

Abbreviations

AG 568: (αZ)-5-Amino-4-cyano-α-[(3,4-dihydroxyphenyl)methylene]-1H-pyrazole-3-acetonitrile
CNS: Central nervous system
Crk: Cellular homolog of oncogene from CT10 avian sarcoma virus
CrkL: Crk-like protein
dlar: Drosophila leukocyte antigen-related protein
Dok1: Downstream of tyrosine kinases 1
EGF: Epithelial growth factor
ena: Enabled
fax: Failed axon connections
PD173955: 6-(2,6-Dichlorophenyl)-8-methyl-2-[[3-(methylthio)phenyl]amino]-Pyrido[2,3-d]pyrimidin-7(8H)-one
PD180970: 6-(2,6-Dichlorophenyl)-2-[(4-fl uoro-3-methylphenyl)amino]-8-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one
p190RhoGAP: 190 kD GTPase activating protein for RhoA
PGDF: Platelet-derived growth factor
Rin1: Ras-interactor 1
Robo: Roundabout

 

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