Structural Positioning of the SH2 Domain Is Critical for Bcr-Abl Kinase Activity, Signal Transduction and Oncogenic Transformation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 569-569
Author(s):  
Oliver D. Hantschel ◽  
Florian Grebien ◽  
Ines Kaupe ◽  
Giulio Superti-Furga
Keyword(s):  
Signal Transduction ◽  
Catalytic Activity ◽  
Kinase Activity ◽  
Critical Factor ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Pharmacological Intervention ◽  
Single Point Mutation ◽  
Mouse Bone Marrow

Abstract We have recently shown that the SH2 domain stimulates c-Abl catalytic activity and substrate phosphorylation. This effect is exerted directly through the establishment of a tight SH2-kinase domain interface in the active conformation of c-Abl (Filippakopoulos et al. (2008) Cell, in press, scheduled to be published on September 5, 2008). Mutations in the SH2 domain that presumably disrupt this SH2-kinase domain interface, such as the Ile164Glu mutation, result in severe impairment of Abl catalytic activity. Thus, correct positioning of the SH2 and kinase domain modules appears to be critical for efficient activation of cytoplasmic tyrosine kinases. Here, we present data showing that the same structural coupling of the SH2 and kinase domain is also a critical factor for full activation of the oncogenic fusion kinase Bcr-Abl. A single point mutation in the SH2 domain (Ile164Glu) led to a dramatic reduction in Bcr-Abl in vitro tyrosine kinase activity and Bcr-Abl autophosphorylation, both on the activation loop (pTyr-412) and the SH2-kinase domain linker (pTyr-245). This resulted in a strong decrease in global cellular tyrosine phosphorylation, as well as decreased phosphorylation of critical downstream mediators of Bcr-Abl signaling. Both wildtype Bcr-Abl, as well as the Bcr-Abl Ile164Glu mutant were able to confer factor independent growth to Ba/F3- and UT-7 cell lines, although to a different extent. Detailed data on the properties of the Ile164Glu mutation in vitro, in imatinib inhibition assays, transformation assays and mouse bone marrow transplant models will be presented. We propose that the structural positioning of the SH2 domain is a crucial factor for constitutive activity, signal transduction and transforming capacity of Bcr-Abl. Besides oligomerization via the N-terminal coiled-coiled domain and loss of the auto-inhibitory N-terminal myristoyl group, the proper positioning of the SH2 domain appears to be another critical factor that is required for constitutive activation of Bcr- Abl, which is the prerequisite for its ability to induce chronic myeloid leukemia (CML). Inhibitors of the SH2-kinase domain interface of Bcr-Abl may comprise alternative or additional points of pharmacological intervention for the treatment of imatinib-sensitive or -resistant CML or Ph+ acute lymphocytic leukemia.

The Bcr-Abl SH2-Kinase Domain Interface Is Critical for Leukemogenesis and An Additional Therapeutic Target in CML.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 37-37
Author(s):  
Oliver D. Hantschel ◽  
Florian Grebien ◽  
Ines Kaupe ◽  
Boris Kovacic ◽  
John Wojcik ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Kinase Activity ◽  
Critical Factor ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Wild Type ◽  
Tyrosine Kinase Activity ◽  
Downstream Signaling

Abstract Abstract 37 We previously showed that the Abl SH2 domain is an allosteric activator of c-Abl tyrosine kinase activity and substrate phosphorylation (Filippakopoulos et al. (2008) Cell 134(5), 793-803). This effect is exerted directly by docking of the SH2 domain onto the N-lobe of the kinase domain in the active conformation of c-Abl. We also showed that the same structural mechanism is a critical factor for full activation of the oncogenic fusion kinase Bcr-Abl. Disruption of binding of the SH2 domain to the kinase domain in Bcr-Abl by the Ile164Glu mutation in the SH2 domain, led to a strong reduction in in vitro tyrosine kinase activity and Bcr-Abl autophosphorylation. Unexpectedly, we observed a differential attenuation of downstream signaling pathways upon disruption of the SH2-kinase domain interface, indicating different activation thresholds of Bcr-Abl downstream signaling pathways. Here, we show that disrupting the SH2-kinase domain interface abrogates the transforming capacity of Bcr-Abl. Cells expressing the Bcr-Abl Ile164Glu mutant were unable to generate cytokine-independent colonies in vitro. Furthermore, mice transplanted with Bcr-Abl Ile164Glu expressing bone marrow cells did not develop the characteristic MPD-like disease that is caused by wild-type Bcr-Abl. Mice that received Bcr-Abl Ile164Glu cells showed normal survival, blood counts and histology after more than 100 days post-transplant, despite the presence of Bcr-Abl Ile164Glu-expressing cells in all blood lineages. This shows that the formation of the SH2-kinase domain interface is strictly necessary for Bcr-Abl to cause CML. Together with our data that show sensitization to imatinib inhibition of Bcr-Abl Ile164Glu as compared to Bcr-Abl wild-type, this argues for the SH2-kinase domain interface as an additional drug target on Bcr-Abl that may synergize with tyrosine kinase inhibitors and may be useful to inhibit tyrosine kinase inhibitor resistant Bcr-Abl clones. To address possibilities to interfere with the SH2-kinase domain interface, we are using an engineered binding protein that binds to the Abl SH2 domain with high-affinity and specificity and supposedly disrupts the interface with the kinase domain, resulting in a decrease in Bcr-Abl kinase activity. In conclusion, we provide strong evidence that the structural positioning of the SH2 domain is a crucial factor for constitutive activity, signal transduction and leukemogenicity of Bcr-Abl. Besides oligomerization via the N-terminal coiled-coiled domain and loss of the auto-inhibitory N-terminal myristoyl group, the proper positioning of the SH2 domain appears to be another critical factor that is required for constitutive activation of Bcr-Abl. Inhibitors of the SH2-kinase domain interface of Bcr-Abl may comprise alternative or additional points of pharmacological intervention for the treatment of imatinib-sensitive or -resistant CML or Ph+ acute lymphocytic leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Negative regulation of Raf-1 by phosphorylation of serine 621.

1996 ◽  
Vol 16 (10) ◽  
pp. 5409-5418 ◽  
Author(s):  
H Mischak ◽  
T Seitz ◽  
P Janosch ◽  
M Eulitz ◽  
H Steen ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Kinase Activity ◽  
Phosphorylation Site ◽  
Kinase Domain ◽  
Negative Regulation ◽  
Catalytic Function ◽  
Dependent Protein ◽  
The One

The elevation of cyclic AMP (cAMP) levels in the cell downregulates the activity of the Raf-1 kinase. It has been suggested that this effect is due to the activation of cAMP-dependent protein kinase (PKA), which can directly phosphorylate Raf-1 in vitro. In this study, we confirmed this hypothesis by coexpressing Raf-1 with the constitutively active catalytic subunit of PKA, which could fully reproduce the inhibition previously achieved by cAMP. PKA-phosphorylated Raf-1 exhibits a reduced affinity for GTP-loaded Ras as well as impaired catalytic activity. As the binding to GTP-loaded Ras induces Raf-1 activation in the cell, we examined which mechanism is required for PKA-mediated Raf-1 inhibition in vivo. A Raf-1 point mutant (RafR89L), which is unable to bind Ras, as well as the isolated Raf-1 kinase domain were still fully susceptible to inhibition by PKA, demonstrating that the phosphorylation of the Raf-1 kinase suffices for inhibition. By the use of mass spectroscopy and point mutants, PKA phosphorylation site was mapped to a single site in the Raf-1 kinase domain, serine 621. Replacement of serine 621 by alanine or cysteine or destruction of the PKA consensus motif by changing arginine 618 resulted in the loss of catalytic activity. Notably, a mutation of serine 619 to alanine did not significantly affect kinase activity or regulation by activators or PKA. Changing serine 621 to aspartic acid yielded a Raf-1 protein which, when expressed to high levels in Sf-9 insect cells, retained a very low inducible kinase activity that was resistant to PKA downregulation. The purified Raf-1 kinase domain displayed slow autophosphorylation of serine 621, which correlated with a decrease in catalytic function. The Raf-1 kinase domain activated by tyrosine phosphorylation could be downregulated by PKA. Specific removal of the phosphate residue at serine 621 reactivated the catalytic activity. These results are most consistent with a dual role of serine 621. On the one hand, serine 621 appears essential for catalytic activity; on the other hand, it serves as a phosphorylation site which confers negative regulation.

scholarly journals Complex Effects of Naturally Occurring Mutations in the JAK3 Pseudokinase Domain: Evidence for Interactions between the Kinase and Pseudokinase Domains

2000 ◽  
Vol 20 (3) ◽  
pp. 947-956 ◽  
Author(s):  
Min Chen ◽  
Alan Cheng ◽  
Fabio Candotti ◽  
Yong-Jie Zhou ◽  
Anka Hymel ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Catalytic Domain ◽  
Intramolecular Interaction ◽  
Severe Combined Immunodeficiency ◽  
Kinase Domain ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT The structure of Janus kinases (JAKs) is unique among protein tyrosine kinases in having tandem, nonidentical kinase and pseudokinase domains. Despite its conservation in evolution, however, the function of the pseudokinase domain remains poorly understood. Lack of JAK3 expression results in severe combined immunodeficiency (SCID). In this study, we analyze two SCID patients with mutations in the JAK3 pseudokinase domain, which allows for protein expression but disrupts the regulation of the kinase activity. Specifically, these mutant forms of JAK3 had undetectable kinase activity in vitro but were hyperphosphorylated both in patients' Epstein-Barr virus-transformed B cells and when overexpressed in COS7 cells. Moreover, reconstitution of cells with these mutants demonstrated that, although they were constitutively phosphorylated basally, they were unable to transmit cytokine-dependent signals. Further analysis showed that the isolated catalytic domain of JAK3 was functional whereas either the addition of the pseudokinase domain or its deletion from the full-length molecule reduced catalytic activity. Through coimmunoprecipitation of the isolated pseudokinase domain with the isolated catalytic domain, we provide the first evidence that these two domains interact. Furthermore, whereas the wild-type pseudokinase domain modestly inhibited kinase domain-mediated STAT5 phosphorylation, the patient-derived mutants markedly inhibited this phosphorylation. We thus conclude that the JAK3 pseudokinase domain is essential for JAK3 function by regulating its catalytic activity and autophosphorylation. We propose a model in which this occurs via intramolecular interaction with the kinase domain and that increased inhibition of kinase activity by the pseudokinase domain likely contributes to the disease pathogenesis in these two patients.

scholarly journals Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop.

1997 ◽  
Vol 17 (5) ◽  
pp. 2497-2501 ◽  
Author(s):  
J Feng ◽  
B A Witthuhn ◽  
T Matsuda ◽  
F Kohlhuber ◽  
I M Kerr ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Kinase Activity ◽  
Critical Role ◽  
Regulatory Region ◽  
Kinase Domain ◽  
Detectable Effect ◽  
Activation Loop ◽  
Receptor Complexes ◽  
Induced Aggregation

The Janus protein tyrosine kinases (Jaks) play critical roles in transducing growth and differentiation signals emanating from ligand-activated cytokine receptor complexes. The activation of the Jaks is hypothesized to occur as a consequence of auto- or transphosphorylation on tyrosine residues associated with ligand-induced aggregation of the receptor chains and the associated Jaks. In many kinases, regulation of catalytic activity by phosphorylation occurs on residues within the activation loop of the kinase domain. Within the Jak2 kinase domain, there is a region that has considerable sequence homology to the regulatory region of the insulin receptor and contains two tyrosines, Y1007 and Y1008, that are potential regulatory sites. In the studies presented here, we demonstrate that among a variety of sites, Y1007 and Y1008 are sites of trans- or autophosphorylation in vivo and in in vitro kinase reactions. Mutation of Y1007, or both Y1007 and Y1008, to phenylalanine essentially eliminated kinase activity, whereas mutation of Y1008 to phenylalanine had no detectable effect on kinase activity. The mutants were also examined for the ability to reconstitute erythropoietin signaling in gamma2 cells, which lack Jak2. Consistent with the kinase activity, mutation of Y1007 to phenylalanine eliminated the ability to restore signaling. Moreover, phosphorylation of a kinase-inactive mutant (K882E) was not detected, indicating that Jak2 activation during receptor aggregation is dependent on Jak2 and not another receptor-associated kinase. The results demonstrate the critical role of phosphorylation of Y1007 in Jak2 regulation and function.

Activation of the proto-oncogene p60c-src by point mutations in the SH2 domain

1990 ◽  
Vol 10 (6) ◽  
pp. 2855-2862
Author(s):  
M C O'Brien ◽  
Y Fukui ◽  
H Hanafusa
Keyword(s):  
Kinase Activity ◽  
Single Point ◽  
Point Mutations ◽  
Soft Agar ◽  
Specific Protein ◽  
Sh2 Domain ◽  
Single Point Mutation ◽  
Src Gene

To investigate the importance of a conserved region spanning residues 137 to 241 in the noncatalytic domain of p60c-src (SH2 region), we used oligonucleotide-directed mutagenesis to change residues that are highly conserved in this region. Chicken embryo fibroblasts infected with a p60c-src variant containing arginine instead of tryptophan at residue 148 (W148R) appeared more rounded than cells overexpressing a normal c-src gene, and they formed colonies in soft agar. p60c-src variants containing serine instead of arginine at residue 155 (R155S) or isoleucine instead of glycine at residue 170 (G170I) also appeared transformed and were anchorage independent, but to a lesser extent than W148R. Mutation of residue 201 from histidine to leucine (H201L) had no observable effect. The in vitro kinase activity of cells infected with W148R or G170I was elevated twofold. Expression of p60W148R (or, to a lesser extent, of p60G170I) increased the number of proteins phosphorylated on tyrosine in infected cells. All of the mutants were phosphorylated in vivo on Tyr-527, instead of Tyr-416 as observed for p60v-src. Immunoprecipitated p60W148R and p60G170I were found to be associated with a phosphatidylinositol kinase activity, a factor which appears to be necessary for transformation by tyrosine-specific protein kinases. These results show that a single point mutation in the SH2 region of the cellular src gene can activate its transforming potential. This type of activation is in a new category of alterations at the amino terminus that activate but do not cause a shift in phosphorylation at the carboxy terminus.

scholarly journals Activation of the proto-oncogene p60c-src by point mutations in the SH2 domain.

1990 ◽  
Vol 10 (6) ◽  
pp. 2855-2862 ◽  
Author(s):  
M C O'Brien ◽  
Y Fukui ◽  
H Hanafusa
Keyword(s):  
Kinase Activity ◽  
Single Point ◽  
Point Mutations ◽  
Soft Agar ◽  
Specific Protein ◽  
Sh2 Domain ◽  
Single Point Mutation ◽  
Src Gene

To investigate the importance of a conserved region spanning residues 137 to 241 in the noncatalytic domain of p60c-src (SH2 region), we used oligonucleotide-directed mutagenesis to change residues that are highly conserved in this region. Chicken embryo fibroblasts infected with a p60c-src variant containing arginine instead of tryptophan at residue 148 (W148R) appeared more rounded than cells overexpressing a normal c-src gene, and they formed colonies in soft agar. p60c-src variants containing serine instead of arginine at residue 155 (R155S) or isoleucine instead of glycine at residue 170 (G170I) also appeared transformed and were anchorage independent, but to a lesser extent than W148R. Mutation of residue 201 from histidine to leucine (H201L) had no observable effect. The in vitro kinase activity of cells infected with W148R or G170I was elevated twofold. Expression of p60W148R (or, to a lesser extent, of p60G170I) increased the number of proteins phosphorylated on tyrosine in infected cells. All of the mutants were phosphorylated in vivo on Tyr-527, instead of Tyr-416 as observed for p60v-src. Immunoprecipitated p60W148R and p60G170I were found to be associated with a phosphatidylinositol kinase activity, a factor which appears to be necessary for transformation by tyrosine-specific protein kinases. These results show that a single point mutation in the SH2 region of the cellular src gene can activate its transforming potential. This type of activation is in a new category of alterations at the amino terminus that activate but do not cause a shift in phosphorylation at the carboxy terminus.

scholarly journals The SH2 Domain of BCR-ABL1 Regulates Kinase Autophosphorylation By Controlling Activation Loop Accessibility

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2209-2209
Author(s):  
Oliver D. Hantschel ◽  
Allan Joaquim Lamontanara ◽  
Sandrine Georgeon ◽  
Giancarlo Tria ◽  
Dmitri Svergun
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Binding Pocket ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Activation Loop ◽  
Phosphorylation Sites

Abstract Chronic myelogenous leukemia (CML) is caused by BCR-ABL1, which is a constitutively active form of the Abelson tyrosine kinase (ABL1). While treatment with the tyrosine kinase inhibitors imatinib, nilotinib, dasatinib, bosutinib or ponatinib that target the ATP binding pocket of BCR-ABL1 leads to durable cytogenetic and molecular remissions in the majority CML patients, primary and secondary drug resistance remains a clinical problem. Targeting additional sites in the BCR-ABL1 kinase outside the highly conserved ATP binding pocket may be an alternative strategy to restrict drug resistance and limit side effects of ATP-competitive drugs with low selectivity. Our recent work has shown that an allosteric intramolecular interaction of the BCR-ABL1 SH2 domain with its kinase domain is critical for leukemogenesis and can be targeted with an engineered high-affinity binding protein. We have now elucidated the molecular mechanisms responsible for the regulation of BCR-ABL1 kinase activity by its SH2 domain: To this end, we set-up an efficient expression system for the BCR-ABL1 SH2-kinase domain unit in E.coli with excellent yield, purity and activity. Detailed biophysical and biochemical analysis of the purified recombinant proteins in vitro recapitulated SH2-dependent regulation of BCR-ABL1 in CML cells and enabled a quantitative enzymatic analysis of BCR-ABL1 activation. Unexpectedly, we found that the interaction of the SH2 domain with the kinase domain is the critical switch that shifts the BCR-ABL1 activation loop from an otherwise closed to a fully open conformation and enables its autophosphorylation. The activation loop is a central and almost universally used control element that regulates the activity of protein kinases, as the conformation and phosphorylation status of the activation loop determines substrate binding to the active site. In BCR-ABL1, activation loop phosphorylation is required for transformation of fibroblasts and haematopoietic progenitors. We show that the SH2-kinase interaction enables autophosphorylation of the activation loop in trans by rendering a key phosphorylation site (Tyr-412) highly accessible. This requires prior phosphorylation of Tyr-245 in the SH2-kinase linker of BCR-ABL1. Mutational disruption of the SH2-kinase interaction abolished activation loop phosphorylation. Importantly, this effect was independent of the phosphotyrosine binding ability of the SH2 domain, which indicated that the SH2 domain is a true allosteric activator of BCR-ABL1 kinase activity. We also show that the spectrum of tyrosine phosphorylation sites that we mapped by mass spectrometry in vitro were vastly overlapping with the observed BCR-ABL1 phosphorylation sites in CML cells indicating that BCR-ABL1 autophosphorylation might be the major mechanism that determines its cellular phosphorylation status. In summary, our study demonstrates a novel mechanism by which a protein-protein interaction domain may allosterically mediate the transition of an inactive to an active kinase conformation in a key oncoprotein. This work may serve as an archetype to identify further allosteric regulatory mechanisms in other tyrosine kinases that are activated in haematological malignancies and facilitate the development of new allosteric inhibitors targeting oncogenic tyrosine kinases. Disclosures No relevant conflicts of interest to declare.

scholarly journals Role for the Ran Binding Protein, Mog1p, in Saccharomyces cerevisiae SLN1-SKN7 Signal Transduction

2004 ◽  
Vol 3 (6) ◽  
pp. 1544-1556 ◽  
Author(s):  
Jade Mei-Yeh Lu ◽  
Robert J. Deschenes ◽  
Jan S. Fassler
Keyword(s):  
Signal Transduction ◽  
Transcription Factor ◽  
Osmotic Stress ◽  
Kinase Activity ◽  
Mitogen Activated Protein Kinase ◽  
Osmotic Response ◽  
Mitogen Activated Protein ◽  
Kinase Pathway

ABSTRACT Yeast Sln1p is an osmotic stress sensor with histidine kinase activity. Modulation of Sln1 kinase activity in response to changes in the osmotic environment regulates the activity of the osmotic response mitogen-activated protein kinase pathway and the activity of the Skn7p transcription factor, both important for adaptation to changing osmotic stress conditions. Many aspects of Sln1 function, such as how kinase activity is regulated to allow a rapid response to the continually changing osmotic environment, are not understood. To gain insight into Sln1p function, we conducted a two-hybrid screen to identify interactors. Mog1p, a protein that interacts with the yeast Ran1 homolog, Gsp1p, was identified in this screen. The interaction with Mog1p was characterized in vitro, and its importance was assessed in vivo. mog1 mutants exhibit defects in SLN1-SKN7 signal transduction and mislocalization of the Skn7p transcription factor. The requirement for Mog1p in normal localization of Skn7p to the nucleus does not fully account for the mog1-related defects in SLN1-SKN7 signal transduction, raising the possibility that Mog1p may play a role in Skn7 binding and activation of osmotic response genes.

scholarly journals Lyn Physically Associates With the Erythropoietin Receptor and May Play a Role in Activation of the Stat5 Pathway

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3734-3745 ◽  
Author(s):  
Hiroshi Chin ◽  
Ayako Arai ◽  
Hiroshi Wakao ◽  
Ryuichi Kamiyama ◽  
Nobuyuki Miyasaka ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Erythropoietin Receptor ◽  
Tyrosine Kinase Domain ◽  
Binding Studies ◽  
In Vitro Binding ◽  
Vitro Binding

Abstract Protein tyrosine phosphorylation plays a crucial role in signaling from the receptor for erythropoietin (Epo), although the Epo receptor (EpoR) lacks the tyrosine kinase domain. We have previously shown that the Jak2 tyrosine kinase couples with the EpoR to transduce a growth signal. In the present study, we demonstrate that Lyn, a Src family tyrosine kinase, physically associates with the EpoR in Epo-dependent hematopoietic cell lines, 32D/EpoR-Wt and F36E. Coexpression experiments in COS7 cells further showed that Lyn induces tyrosine phosphorylation of the EpoR and that both LynA and LynB, alternatively spliced forms of Lyn, bind with the membrane-proximal 91-amino acid region of the EpoR cytoplasmic domain. In vitro binding studies using GST-Lyn fusion proteins further showed that the Src homology (SH)-2 domain of Lyn specifically binds with the tyrosine-phosphorylated EpoR in lysate from Epo-stimulated cells, whereas the tyrosine kinase domain of Lyn binds with the unphosphorylated EpoR. Far-Western blotting and synthetic phosphopeptide competition assays further indicated that the Lyn SH2 domain directly binds to the tyrosine-phosphorylated EpoR, most likely through its interaction with phosphorylated Y-464 or Y-479 in the carboxy-terminal region of the EpoR. In vitro binding studies also demonstrated that the Lyn SH2 domain directly binds to tyrosine-phosphorylated Jak2. In vitro reconstitution experiments in COS7 cells further showed that Lyn induces tyrosine phosphorylation of Stat5, mainly on Y-694, and activates the DNA-binding and transcription-activating abilities of Stat5. In agreement with this, Lyn enhanced the Stat5-dependent transcriptional activation when overexpressed in 32D/EpoR-Wt cells. In addition, Lyn was demonstrated to phosphorylate the EpoR and Stat5 on tyrosines in vitro. These results suggest that Lyn may play a role in activation of the Jak2/Stat5 and other signaling pathways by the EpoR.

Nuclear receptor-binding protein 1: a novel tumour suppressor and pseudokinase

2013 ◽  
Vol 41 (4) ◽  
pp. 1055-1060 ◽  
Author(s):  
Jason S. Kerr ◽  
Catherine H. Wilson
Keyword(s):  
Nuclear Receptor ◽  
Receptor Binding ◽  
Kinase Activity ◽  
Binding Protein ◽  
Kinase Domain ◽  
Present Review ◽  
Critical Components ◽  
Receptor Binding Protein

Pseudokinases are a class of kinases which are structurally designated as lacking kinase activity. Despite the lack of kinase domain sequence conservation, there is increasing evidence that a number of pseudokinases retain kinase activity and/or have critical cellular functions, casting aside previous notions that pseudokinases simply exist as redundant kinases. Moreover, a number of recent studies have implicated pseudokinases as critical components in cancer formation and progression. The present review discusses the interactions and potential functions that nuclear receptor-binding protein 1, a pseudokinase recently described to have a tumour-suppressive role in cancer, may play in cellular homoeostasis and protein regulation. The recent findings highlighted in the present review emphasize the requirement to fully determine the function of pseudokinases in vitro and in vivo, the understanding of which may ultimately uncover new directions for drug discovery.

Sign in / Sign up

Export Citation Format

Share Document