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Enzyme Nomenclature
Information on EC 2.7.10.2 - non-specific protein-tyrosine kinase
for references in articles please use BRENDA:EC2.7.10.2
Word Map on EC 2.7.10.2
- 2.7.10.2
- leukemia
-
integrins
- imatinib
- carcinoma
- vascular
-
myelogenous
- inflammatory
-
mitogen-activated
- metastasis
-
philadelphia
-
3-kinase
-
cytogenetic
- cytoskeleton
-
mapks
-
autophosphorylation
- t-cells
- sh2
- dasatinib
- lymphoma
- mesylate
- hematologic
- phosphatidylinositol
- collagen
- lymphoblastic
- phosphotyrosine
- fibronectin
- adhesions
-
angiogenesis
-
paxillin
-
stats
-
myeloproliferative
-
signal-regulated
-
remiss
-
tyrosine-phosphorylated
- neoplasm
-
allogeneic
-
mitogen
-
platelet-derived
-
dominant-negative
-
relapse
-
adaptor
-
oncoproteins
-
integrin-mediated
-
kinase-dependent
-
breakpoints
-
factor-beta
- rhoa
- crisis
-
activins
- drug development
- synthesis
- medicine
- pdgfr
- pharmacology
- analysis
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The enzyme appears in viruses and cellular organisms
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EC NUMBER 
COMMENTARY 
2.7.10.2
-
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RECOMMENDED NAME
GeneOntology No.
non-specific protein-tyrosine kinase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
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-
-
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ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
regulation of enzyme activity involves the activation loop, a polypeptide region outside the active site cleft, which is reversibly phosphorylated
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ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
reaction mechanism
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ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
structure-function relationship, active site structure, catalytic mechanism and enzyme regulation, overview
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ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
structure-function relation ship, active site structure, catalytic mechanism involving the catalytic base Asp386 and enzyme regulation, overview
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ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
structure-function relationship, active site structure, catalytic mechanism and enzyme regulation, overview
-
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
catalytic mechanism
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ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
substrate binding site involving residues R279, R281, and R283, more distant residues S280, F382, S273, and D276 are also important for activity
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ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
residue W1038 is essential for catalytic activity
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho group transfer
phospho group transfer
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-
-
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phospho group transfer
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-
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SYSTEMATIC NAME
IUBMB Comments
ATP:[protein]-L-tyrosine O-phosphotransferase (non-specific)
Unlike EC 2.7.10.1, receptor protein-tyrosine kinase, this protein-tyrosine kinase does not have a transmembrane domain. In the human genome, 32 non-specific protein-tyrosine kinases have been identified and these can be divided into ten families [1].
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CAS REGISTRY NUMBER
COMMENTARY
114051-78-4
p56lck protein kinase
80449-02-1
protein-tyrosine kinase
9026-43-1
this CAS Reg. No. encompasses a great variety of protein kinases including the serine/threonine specific kinases
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
strain HT-1, overproduced in Escherichia coli under the control of phage lambda promoter
SwissProt
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SwissProt
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490048, 490049, 490050, 490051, 490052, 490053, 490054, 490055, 490056, 490057, 490058, 490059, 691262, 737723
SwissProt
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SwissProt
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SwissProt
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SwissProt
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660885, 660948, 660970, 661069, 661180, 661230, 661273, 661366, 661392, 661396, 661457, 661461, 661487, 661540, 661548, 661726, 661749, 662130, 662138, 662139, 662172, 662174, 662236, 662556, 662672, 662838, 662854, 662858, 663021, 663196, 663291, 663436, 671209, 671253, 672104, 672781, 672954, 672975, 673029, 673223, 673441, 673467, 673700, 673959, 674057, 674376, 674620, 674681, 674685, 674767, 674865, 674876, 674905, 675097, 675205, 675547, 675624, 676266, 676883, 690302, 690368, 690415, 691086, 691143, 691297, 691312, 691455, 691457, 691651, 693137, 693315, 693456, 693870, 694084, 694492, 695228, 701645, 702439, 703579, 703984, 703985, 704787, 705448, 705664, 705895, 705943, 705953, 706405, 706765, 706766, 721489, 722050, 722900, 723508, 723518, 723552, 723583, 723632, 737321, 737757, 738373, 738408, 738649, 738650, 738741, 738876, 739714
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c-Abl, two splice variants, one c-Abl 1b that is N-terminally myristoylated, and another that is 19 residues shorter at the N-terminus and not known to be myristoylated
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strain HT-1, overproduced in Escherichia coli under the control of phage lambda promoter
SwissProt
-
SwissProt
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
malfunction
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mutations of JAK3 may be a cause of severe combined immunodeficiency
malfunction
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mutations of JAK3 may be a cause of severe combined immunodeficiency, JAK3 knockout mice have a profound reduction in thymic progenitor cells and reduced ability to reconstitute T cell development, in the periphery, CD8+ T and NK cells are severely reduced. JAK3- (and gamma chain) deficient mice also have severely defective B cell development, deficiency of JAK1 and JAK2 is lethal
malfunction
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deficiency of Jak3 or Tyk2 results in defined clinical disorders, a striking phenotype associated with inactivating Jak3 mutations is severe combined immunodeficiency syndrome, whereas mutation of Tyk2 results in autosomal recessive hyperimmunoglobulin E syndrome, complete deletion of Jak1 or Jak2 in the mouse are not compatible with life and do not have counterparts in human disease. Activating mutations of each of the Jaks are found in association with malignant transformation, the most common being gain-of-function mutations of Jak2 in polycythemia vera and other myeloproliferative disorders.
malfunction
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deficiency of Jak3 or Tyk2 results in defined clinical disorders, a striking phenotype associated with inactivating Jak3 mutations is severe combined immunodeficiency syndrome, whereas mutation of Tyk2 results in autosomal recessive hyperimmunoglobulin E syndrome, complete deletion of Jak1 or Jak2 in the mouse are not compatible with life and do not have counterparts in human disease. Activating mutations of each of the Jaks are found in association with malignant transformation, the most common being gain-of-function mutations of Jak2 in polycythemia vera and other myeloproliferative disorders. Jak1 knockout mice have major deficits in lymphopoiesis and a failure to respond to signals from class II cytokine receptors, gammac cytokine receptors, and cytokine receptors that contain the gp130 subunit. Jak2 deficiency is lethal.
malfunction
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only 75% of ABL1 knockout mice survive the first week,33 the remaining animals show severe defects in spermatogenesis, thymic and splenic atrophy, susceptibility to infections and reductions of T- and B-cell lymphocytes and their early precursors in lymphoid organs
malfunction
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enzyme loss causes a reduction in ring canal diameter within germline cysts
malfunction
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enzyme-deficiency leads to a reduction in mature peripheral B cells. Enzyme-deficient mice fail to respond to immunization with type 2 thymus-independent antigens, and accordingly, peripheral B cells from these animals are unresponsive to B cell receptor crosslinking
physiological function
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JAK3 associates with the common gamma chain cytokine receptor, Tyk2 is involved in signaling by type I interferons, interleukin-12 and interleukin-23
physiological function
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JAK3 associates with the common gamma chain cytokine receptor, Tyk2 is involved in signaling by type I interferons, interleukin-12 and interleukin-23
physiological function
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JAK1 and JAK2 activate c-Myc promoter in interleukin 5 signaling
physiological function
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ABL1 binds to the actin cytoskeleton and is involved in cytoskeletal organization, non-erythroid myelopoiesis and regulation of small GTPases, in response to genotoxic stress such as DNA damage or the increase of reactive oxygen species, ABL1 is translocated into the nucleus where its activity contributes to induction of apoptosis and inhibition of cell growth
physiological function
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ABL1 binds to the actin cytoskeleton and is involved in cytoskeletal organization, non-erythroid myelopoiesis and regulation of small GTPases, in response to genotoxic stress such as DNA damage or the increase of reactive oxygen species, ABL1 is translocated into the nucleus where its activity contributes to induction of apoptosis and inhibition of cell growth
physiological function
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JAK-STAT signaling is required for germline stem cell and cyst progenitor cells maintenance in testis
physiological function
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crucial for cytokine receptor signaling in blood formation and immune responses
physiological function
constitutive JAK activation leads to persistent activation of STAT transcription factors, and several cancers exhibit constitutive STAT activation, in the absence of JAK or STAT activating mutations
physiological function
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lymphocyte-specific protein tyrosine kinase LCK is involved in the fractionated radiation-induced expansion of the glioma-initiating cell population and acquisition of resistance to anticancer treatments. Fractionated radiation causes a selective increase in the activity of LCK. The activities of other Src family kinases Src, Fyn, and Lyn are not significantly increased. Knockdown of LCK expression with siRNA effectively block fractionated radiation-induced expansion of the CD133+ cell population. siRNA targeting of LCK also suppresses fractionated radiation-induced expression of the glioma stem cell marker proteins CD133, Nestin, and Musashi. Expression of the proteins Notch2 and Sox2 in glioma cells treated with fractionated radiation is also downregulated by LCK inhibition. siRNA-mediated knockdown of LCK effectively restores the sensitivity of glioma cells to cisplatin and etoposide
physiological function
interaction of the Src homology 3 domain SH3 with the epidermal growth factor receptor-binding domain in isoform ACK1 leads to auto-inhibition of the kinase activity. Release of this auto-inhibition is a key step for activation of ACK1. Mutation of the SH3 domain causes activation of ACK1, independent of cell adhesion. A region at the N-terminus of ACK1, Leu10-Leu14, is essential for cell adhesion-mediated activation. In the activation of ACK1 by epidermal growth factor receptor signalling, growth-factor-receptor-bound protein Grb2 mediates the interaction of ACK1 with epidermal growth factor receptor through binding to the epidermal growth factor receptor-binding domain and activates ACK1 by releasing the auto-inhibition
physiological function
non-receptor tyrosine kinase Fer is able to phosphorylate RhoGDIalpha, regulator of the small GTPase Rac, and form a direct protein complex with it. This interaction is mediated by the C-terminal end of RhoGDIalpha. Tyrosine phosphorylation of RhoGDIalpha by Fer prevents subsequent binding of Rac to RhoGDIalpha, but once a RhoGDIalpha-Rac complex is formed, the Fer kinase is not able to cause Rac release through tyrosine phosphorylation of preformed RhoGDIalpha-Rac complexes
physiological function
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specific pharmacological inhibition and genetic silencing indicate the involvement of isoform Lck in the regulation of neuritic outgrowth. Specific Lck inhibition also selectively impairs the long-term hippocampal synaptic plasticity without affecting spontaneous excitatory synaptic transmission or short-term synaptic potentiation and significantly alters hippocampus-dependent spatial learning and memory in vivo
physiological function
murine Btk-/- natural killer cells have decreased innate immune responses to the toll-like receptor TLR3 ligand, with reduced expressions of IFN-gamma, perforin, and granzyme-B and decreased cytotoxic activity. Isoform Btk promotes TLR3-triggered natural killer cell activation mainly by activating the NF-kappaB pathway. Poly(I:C)-induced natural killer cell-mediated acute hepatitis is attenuated in Btk-/- mice or the mice with in vivo administration of Btk inhibitor. Correspondingly, liver damage is aggravated in Btk-/- mice after the adoptive transfer of Btk-/- natural killer cells
physiological function
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isoform c-Abl kinase is required for neutrophil recruitment in vivo and migration in vitro, and the inhibition of c-Abl kinase activity has a significant impact on neutrophil migratory behavior. c-Abl kinase activation depends on 2 integrin engagement, and the activated c-Abl kinase further regulates actin polymerization and membrane protrusion dynamics at the extended leading edges during neutrophil migration. The Rho guanine exchange factor Vav1 is a major downstream effector of c-Abl kinase. The C-terminal SH3-SH2-SH3 domain and proline-rich region of Vav1 are required for its interaction with c-Abl kinase, and c-Abl kinase probably regulates the activity of Vav1 by direct phosphorylation at Tyr-267 in the Dbl homology domain
physiological function
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selective Src-kinase inhibitors 4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo[3,4-d]pyrimidine and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, at 5 microM, attenuate acetylcholine-induced ionic currents and intracellular Ca2+ ion concentration transients in major pelvic ganglion neurons. Blocking the tyrosine kinase activity of Src kinase by pp60 c-src inhibitory peptide also reduces the acetylcholine-induced currents. Sodium orthovanadate, at 200 microM, a tyrosine phosphatase inhibitor, significantly augments the acetylcholine-induced currents
physiological function
Src kinase plays an important role in angiotensin II-elicited protein kinase C zeta activation and the subsequent downstream signaling including ERK1/2 activation and vascular smooth muscle cell proliferation. Angiotensin II induces rapid activation of protein kinase C zeta, which is associated with its phosphorylation and nuclear translocation. angiotensin II not only induces activation by Src, but also promotes the physical association between Src and protein kinase C zeta, which is abolished by Src inhibition with inhibitor 4-amino-5-(4-chlorophenyl)-7-(tert-butyl)pyrazolo[3,4-d]pyrimidine. Src inhibition also abrogates angiotensin II-stimulated protein kinase C zeta activation, ERK1/2 phosphorylation and vascular smooth muscle cell proliferation
physiological function
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Src family tyrosine kinase activation is a required step in non-capacitative cation entry activation. Application of specific inhibitor 4-amino-5-(4-chlorophenyl)-7-(tert-butyl)pyrazolo[3,4-d]pyrimidine completely abolishes thrombin-induced non-capacitative cation entry into platelets, a Ca2+ entry pathway that is independent of Ca2+ store depletion
physiological function
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Src family kinases are important for a balanced production of inflammatory cytokines by human monocyte-derived dendritic cells upon stimulation of toll-like receptors TLR3 and TLR8 with their respective agonists. Disruption of this equilibrium through pharmacological inhibition of Src kinases alters the dendritic cell maturation pattern. While expression of interleukin IL-12 and other inflammatory cytokines depends on Src kinases, the induction of IL-23 and co-stimulatory molecules does not. Dendritic cells treated with Src inhibitors are not compromised in their ability to induce CD4 T cell proliferation and to promote the T helper cell Th17 subset survival but are less efficient in inducing T helper cell Th1 differentiation
physiological function
in HT29 colon carcinoma cells, silencing of tyrosine kinase c-Yes, but not of kinase c-Src, selectively leads to an increase of cell clustering associated with a localisation of beta-catenin at cell membranes and a reduction of expression of beta-catenin target genes. c-Yes silencing induces an increase in apoptosis, inhibition of growth in soft-agar and in mouse xenografts, inhibition of cell migration and loss of the capacity to generate liver metastases in mice. Reintroduction of c-Yes, but not c -Src, restores transforming properties of c-Yes depleted cells. c-Yes kinase activity is required for its role in beta-catenin localisation and growth in soft agar, whereas kinase activity is dispensable for its role in cell migration. c-Yes regulates specific oncogenic signalling pathways important for colon cancer progression that are not shared with c-Src
physiological function
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Notch-1-Furin interaction is regulated by the non-receptor tyrosine kinase, c-Src. c-Src and Notch-1 are physically associated, and this association is responsible for Notch-1 processing and activation. Growth factor TGF-alpha, an epidermal growth factor receptor ligand, and PDGF-BB, a platelet derived growth factor receptor ligand, induce the Notch-1-Furin interaction mediated by c-Src. The association between Notch-1 and Furin is a well-regulated process, extracellular growth factor signals regulate this interaction, which is mediated by c-Src, and there is cross-talk between the plasma growth factor receptor-c-Src and Notch pathways
physiological function
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conditional knockout of isoform c-Abl in the nervous system prevents the phosphorylation of substrate parkin, the accumulation of parkin substrates aminoacyl-tRNA synthetase-interacting multifunctional protein type 2, AIMP2, and fuse-binding protein 1, FBP, and subsequent neurotoxicity in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication
physiological function
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mitochondrial Src tyrosine kinase plays a role in the cardioprotective effect of ischemic preconditioning by modulating complex I activity and mitochondrial reactive oxygen species generation
physiological function
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tyrosine kinase Lyn is critical for TLR2-mediated NF-kappaB activation through the PI 3-kinase signaling pathway
physiological function
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enzyme expression of specific SFK or Ack1 can drive the formation of prostate cancer or progression to castration-recurrent prostate cancer
physiological function
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tyrosine kinase c-Abl promotes homeodomain-interacting protein kinase 2 accumulation and activation in response to DNA damage
physiological function
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JAK tyrosine kinases control integrin activation and dependent lymphocyte trafficking by bridging chemokine receptors to the concurrent and hierarchical activation of the Rho and Rap modules of integrin activation
physiological function
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the enzyme controls actin dynamics to mediate proper ring canal formation during incomplete cytokinesis during germline cyst development in vivo
physiological function
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enzyme expression in a majority of cholangiocarcinoma can interact with receptor tyrosine kinases, augmenting growth and interfering with proliferation inhibitors
physiological function
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the enzyme is essential for B cell activation and differentiation
physiological function
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the enzyme influences neuronal differentiation via a chronic regulation of Na+ channel functionality. The tonic enzyme activity is also critical for normal development of functional Na+ channels and neuronal differentiation or maturation of embryonic stem cells
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + a [homeodomain-interacting protein kinase 2]-L-tyrosine
ADP + a [homeodomain-interacting protein kinase 2]-L-tyrosine phosphate
-
-
-
-
?
ATP + a [Tyr-2 peptide]-L-tyrosine
ADP + a [Tyr-2 peptide]-L-tyrosine phosphate
-
-
-
-
?
ATP + biotin-GGEAIYAAPFKK-amide
ADP + phosphorylated biotin-GGEAIYAAPFKK-amide
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a peptide with the preferred c-Abl substrate sequence carrying an Nterminal biotin
-
-
?
ATP + casein
ADP + phosphocasein
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serine/threonine kinase activity, and no tyrosine kinase activity
-
-
?
ATP + Cbp
? + ADP
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murine Csk binding protein, Cbp, amino acids 74-474, substrate used in kinase activity assay
-
-
?
ATP + cdc2(6-20) peptide
?
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i.e. KVEKIGEGTYGVVYK, substrate of Src family kinases
-
-
?
ATP + cyclin-associated cyclin-dependent kinase
ADP + phosphorylated cyclin-associated cyclin-dependent kinase
ATP + EEEEYIQ[dP]-8-hydroxy-5-(N,N-dimethylsulfonamido)-2-methylquinoline-G
ADP + EEEEYIQ[dP]-8-hydroxy-5-(N,N-dimethylsulfonamido)-2-methylquinoline-G phosphate
-
Y7 Sox-based substrate, kinetic assay
-
-
?
ATP + enolase
ADP + ?
-
serine/threonine kinase activity, and no tyrosine kinase activity
-
-
?
ATP + epidermal growth factor receptor
ADP + phospho-L-tyrosinyl-epidermal growth factor receptor
ATP + F peptide
ADP + phospho-L-tyrosinyl-F peptide
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i.e. biotin-Aca-AAAEEIFGEI-NH2
-
-
?
ATP + GAPEVIYATPGAKKK
ADP + GAPEVI-phosphotyrosinyl-ATPGAKKK
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consensus substrate
-
-
?
ATP + GGEAIYAAPFKK
ADP + GGEAIYAAPFKK phosphate
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kinase assay using biotinylated model substrate peptide
-
-
?
ATP + glycogen synthase kinase 3beta
ADP + phosphotyrosinyl glycogen synthase kinase 3beta
ATP + histone
ADP + phosphorylated histone
serine/threonine-specific kinase activity
-
-
?
ATP + KVEKIGEGTYGVVYK
? + ADP
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substrate peptide used in kinase activity assay, derived from p34cdc2
-
-
?
ATP + lysozyme-L-tyrosine
ADP + lysozyme-L-tyrosine phosphate
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substrate of Src, low activity with Csk or Chk
-
-
?
ATP + myosin light chain
ADP + ?
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serine/threonine kinase activity, and no tyrosine kinase activity
-
-
?
ATP + NaV1.2 channel
ADP + phospho-L-tyrosinyl-NaV1.2 channel
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Y66 and Y1893, which are in consensus sequences appropriate for binding to the Fyn SH2 domain after phosphorylation, are both required for optimal binding and regulation by Fyn. Y730, which is located near the SH3-binding motif in LI-II, and Y1497 and Y1498 in the inactivation gate in LIII-IV, are also required for optimal regulation, but phosphorylation of these sites likely promotes fast inactivation
-
-
?
ATP + P1 peptide
ADP + phospho-L-tyrosinyl-P1 peptide
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i.e. biotin-Aca-AAAEEIpYGEI-NH2
-
-
?
ATP + peptide
ADP + phospho-L-tyrosinyl-peptide
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PTKs phosphorylate substrates in a sequence-specific manner, relatively short peptide sequences determine selectivity, substrate specificity analysis using 144 different peptides, overview
-
-
?
ATP + poly(Glu,Tyr)
? + ADP
-
substrate used in the tyrosine kinase asssay
-
-
?
ATP + poly-(Tyr-Glu)
ADP + phospho-poly-(Tyr-Glu)
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tyrosine kinase substrate, phosphoryated by Swe1p, Mps1p, Ime2p, and Hrr25p, but not by Ste7p, Rad53p, or Mck1p
-
-
?
ATP + protein
?
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CSK phosphorylates other members of the src-family of tyrosine kinases at their regulatory carboxy-terminus. By regulating the activity of these kinases, CSK may play an important role in cell growth and development
-
-
?
ATP + protein tyrosine kinase Yes
ADP + phospho-L-tyrosinyl Yes
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Csk inactivates the enzyme substrate
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-
?