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PubMed2006

Regulatory effects of mammalian target of rapamycin-activated pathways in type I and II interferon signaling.

The mechanisms regulating initiation of mRNA translation for the generation of protein products that mediate interferon (IFN) responses are largely unknown. We have previously shown that both Type I and II IFNs engage the mammalian target of rapamycin (mTOR), resulting in downstream phosphorylation and deactivation of the translational repressor 4E-BP1 (eIF4E-binding protein 1). In the current study, we provide direct evidence that such regulation of 4E-BP1 by IFNalpha or IFNgamma results in sequential dissociation of 4E-BP1 from eukaryotic initiation factor-4E and subsequent formation of a functional complex between eukaryotic initiation factor-4E and eukaryotic initiation factor-4G, to allow initiation of mRNA translation. We also demonstrate that the induction of key IFNalpha- or IFNgamma-inducible proteins (ISG15 (interferon-stimulated gene 15) and CXCL10) that mediate IFN responses are enhanced in 4E-BP1 (4E-BP1(-/-)) knockout MEFs, as compared with wild-type 4E-BP1(+/+) MEFs. On the other hand, IFN-dependent transcriptional regulation of the Isg15 and Cxcl10 genes is intact in the absence of 4E-BP1, as determined by real time reverse transcriptase-PCR assays and promoter assays for ISRE and GAS, establishing that 4E-BP1 plays a selective negative regulatory role in IFN-induced mRNA translation. Interestingly, the induction of expression of ISG15 and CXCL10 proteins by IFNs was also strongly enhanced in cells lacking expression of the tuberin (TSC2(-/-)) or hamartin (TSC1(-/-)) genes, consistent with the known negative regulatory effect of the TSC1-TSC2 complex on mTOR activation. In other work, we demonstrate that the induction of an IFN-dependent antiviral response is strongly enhanced in cells lacking expression of 4E-BP1 and TSC2, demonstrating that these elements of the IFN-activated mTOR pathway exhibit important regulatory effects in the generation of IFN responses. Taken altogether, our data suggest an important role for mTOR-dependent pathways in IFN signaling and identify 4E-BP1 and TSC1-TSC2 as key components in the generation of IFN-dependent biological responses.

Adaptor Proteins, Signal Transducing↗

PubMed1995

Interactions of Cbl with Grb2 and phosphatidylinositol 3'-kinase in activated Jurkat cells.

T-cell receptor (TCR) cross-linking increases tyrosine phosphorylation of multiple proteins, only a few of which have been identified. One of the most rapidly tyrosine-phosphorylated polypeptides is the 120-kDa product of the proto-oncogene c-cbl, a cytosolic and cytoskeletal protein containing multiple proline-rich motifs that are potential binding sites for proteins containing Src homology 3 (SH3) domains. We report here that in cultured Jurkat T cells, Cbl is coprecipitated with antibody against the adapter protein Grb2. Upon activation of Jurkat T cells via the TCR-CD3 complex, we find that high-affinity binding of Cbl requires the N-terminal SH3 domain of GST-Grb2 fusion protein but after cross-linking of the TCR-CD3 and CD4 receptors, Cbl binds equally to its SH2 domain. Grb2 antisera also precipitated p85 from serum-starved cells, while TCR activation increased p85 and tyrosine-phosphorylated Cbl but not Cbl protein in Grb2 immunocomplexes. Phosphatidylinositol (PI) 3-kinase activity was immunoprecipitated from serum-starved cells with Cbl and to a lesser extent with Grb2 antisera, and TCR cross-linking increased this activity severalfold. The PI 3-kinase activity associated with Cbl amounted to 5 to 10% of the total cellular activity that could be precipitated by p85 antisera. The Ras exchange factor Son-of-sevenless 1 (Sos-1) was not found in anti-Cbl immunoprecipitates from activated cells, and Cbl was not detectable in anti-Sos-1 precipitates, supporting the likelihood that Sos-Grb2 and Cbl-Grb2 are present as distinct complexes. Taken together, these data suggest that Cbl function in Jurkat T cells involves its constitutive association with Grb2 and its recruitment of PI 3-kinase in response to TCR activation.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Supercomplex formation between Mlh1-Mlh3 and Sgs1-Top3 heterocomplexes in meiotic yeast cells.

The genome of Saccharomyces cerevisia encodes four mismatch repair MutL proteins and these proteins form three heterocomplexes: Mlh1-Mlh2, Mlh1-Mlh3, and Mlh1-Pms1. Only, the Mlh1-Mlh3 heterocomplex has been implicated specifically in promotion of meiotic crossing-over. In this report, we show that yeast Mlh3 co-immunoprecipitates with Sgs1 helicase in sporulating cells at late stage of meiotic prophase I. Sgs1, a member of the RecQ DNA helicase family, appears to form a stable complex with topoisomerase III (Top3) during meiosis. We suggest that Mlh1-Mlh3 heterocomplex may act as a molecular matchmaker to coordinate Sgs1-Top3 complex in the resolution of meiotic recombination intermediates.

Adaptor Proteins, Signal Transducing↗

PubMed1996

Adhesion through the interaction of lymphocyte function-associated antigen-1 with intracellular adhesion molecule-1 induces tyrosine phosphorylation of p130cas and its association with c-CrkII.

The B-lymphoblastoid cell line JY undergoes homotypic aggregation in a lymphocyte function-associated antigen-1 (LFA-1)-mediated, intracellular adhesion molecule-1 (ICAM-1)-dependent manner when stimulated with phorbol 12-myristate 13-acetate or anti-LFA-1 antibodies. Under conditions that lead to cell aggregation, we observed rapid tyrosine phosphorylation of p130cas, a protein previously identified to be phosphorylated on tyrosine in both v-src- and v-crk-transformed cells. Phosphorylation of p130cas was dependent on binding of LFA-1 to its ligand, ICAM-1, as demonstrated by the use of anti-ICAM-1 antibodies. Several observations suggest that this event may be an important step in the signaling pathway initiated by LFA-1. p130cas phosphorylation was rapidly reversible upon disengagement of the LFA-1-ICAM-1 complex and required cell adhesion since binding of phorbol 12-myristate 13-acetate-stimulated JY cells to purified ICAM-1 or cross-linking of either LFA-1 or ICAM-1 was not sufficient to induce phosphorylation of p130cas. The integrin-stimulated phosphorylation of p130cas created binding sites that were recognized in vitro by the SH2 domain of c-CrkII, a key adaptor protein involved in cell differentiation and transformation. Moreover, we also showed that the LFA-1-stimulated tyrosine phosphorylation of p130cas induces the formation of a p130cas.CrkII and p130cas.CrkL complex in intact cells. This observation suggests that adhesion mediated by the interaction of LFA-1 and ICAM-1 initiates a signaling cascade that involves the activation of protein tyrosine kinases and leads to the regulation of protein-protein interaction via SH2 domains, a key process shared with growth factor signaling pathways.

Antibodies↗

PubMed2002

Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis.

The mu 2 subunit of the AP2 complex is known to be phosphorylated in vitro by a copurifying kinase, and it has been demonstrated recently that mu 2 phosphorylation is required for transferrin endocytosis (Olusanya, O., P.D. Andrews, J.R. Swedlow, and E. Smythe. 2001. Curr. Biol. 11:896-900). However, the identity of the endogenous kinase responsible for this phosphorylation is unknown. Here we identify and characterize a novel member of the Prk/Ark family of serine/threonine kinases, adaptor-associated kinase (AAK)1. We find that AAK1 copurifies with adaptor protein (AP)2 and that it directly binds the ear domain of alpha-adaptin in vivo and in vitro. In neuronal cells, AAK1 is enriched at presynaptic terminals, whereas in nonneuronal cells it colocalizes with clathrin and AP2 in clathrin-coated pits and at the leading edge of migrating cells. AAK1 specifically phosphorylates the mu subunit in vitro, and stage-specific assays for endocytosis show that mu phosphorylation by AAK1 results in a decrease in AP2-stimulated transferrin internalization. Together, these results provide strong evidence that AAK1 is the endogenous mu 2 kinase and plays a regulatory role in clathrin-mediated endocytosis. These results also lend support to the idea that clathrin-mediated endocytosis is controlled by cycles of phosphorylation/desphosphorylation.

Adaptor Protein Complex 2↗

PubMed2006

Architecture of the vimentin cytoskeleton is modified by perturbation of the GTPase ARF1.

Intermediate filaments are required for proper membrane protein trafficking. However, it remains unclear whether perturbations in vesicular membrane transport result in changes in the architecture of the vimentin cytoskeleton. We find that treatment of cells with Brefeldin A, an inhibitor of specific stages of membrane transport, causes changes in the organization of vimentin filaments. These changes arise from movement of pre-existing filaments. Brefeldin A treatment also leads to alterations in the microtubule cytoskeleton. However, this effect is not observed in cells lacking intermediate filaments, indicating that microtubule bundling is downstream of perturbations in the vimentin cytoskeleton. Brefeldin A-induced changes in vimentin architecture are probably mediated through its effects on ADP-ribosylation factor 1 (ARF1). Expression of a dominant-negative mutant of ARF1 induces BFA-like modifications in vimentin morphology. The BFA-dependent changes in vimentin architecture occurred concurrently with the release of the ARF1-regulated adaptor complexes AP-3 and AP-1 from membranes and adaptor redistribution to vimentin networks. These observations indicate that perturbation of the vesicular membrane transport machinery lead to reciprocal changes in the architecture of vimentin networks.

ADP-Ribosylation Factor 1↗

PubMed2002

Patterns of meiotic recombination in human fetal oocytes.

Abnormal patterns of meiotic recombination (i.e., crossing-over) are believed to increase the risk of chromosome nondisjunction in human oocytes. To date, information on recombination has been obtained using indirect, genetic methods. Here we use an immunocytological approach, based on detection of foci of a DNA mismatch-repair protein, MLH1, on synaptonemal complexes at prophase I of meiosis, to provide the first direct estimate of the frequency of meiotic recombination in human oocytes. At pachytene, the stage of maximum homologous chromosome pairing, we found a mean of 70.3 foci (i.e., crossovers) per oocyte, with considerable intercell variability (range 48-102 foci). This mean equates to a genetic-map length of 3,515 cM. The numbers and positions of foci were determined for chromosomes 21, 18, 13, and X. These chromosomes yielded means of 1.23 foci (61.5 cM), 2.36 foci (118 cM), 2.5 foci (125 cM), and 3.22 foci (161 cM), respectively. The foci were almost invariably located interstitially and were only occasionally located close to chromosome ends. These data confirm the large difference, in recombination frequency, between human oocytes and spermatocytes and demonstrate a clear intersex variation in distribution of crossovers. In a few cells, chromosomes 21 and 18 did not have any foci (i.e., were presumptively noncrossover); however, configurations that lacked foci were not observed for chromosomes 13 and X. For the latter two chromosome pairs, the only instances of absence of foci were observed in abnormal cells that showed chromosome-pairing errors affecting these chromosomes. We speculate that these abnormal fetal oocytes may be the source of the nonrecombinant chromosomes 13 and X suggested, by genetic studies, to be associated with maternally derived chromosome nondisjunction.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Act1, an NF-kappa B-activating protein.

Use of an NF-kappaB-dependent selectable marker facilitated the isolation of a cell line containing a cDNA encoding Act1, an NF-kappaB activator. Act1 associates with and activates IkappaB kinase (IKK), leading to the liberation of NF-kappaB from its complex with IkappaB. Many signaling pathways that liberate NF-kappaB also activate activating transcription factor (ATF) and activator protein 1 (AP-1) through Jun kinase (JNK). Act1 also activates JNK, suggesting that it might be part of a multifunctional complex involved in the activation of both NF-kappaB and JNK. Act1 fails to activate NF-kappaB in an IL-1-unresponsive mutant cell line in which all known signaling components are present, suggesting that it interacts with an unknown component in IL-1 signaling.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Phosphorylation of the Grb2- and phosphatidylinositol 3-kinase p85-binding p36/38 by Syk in Lck-negative T cells.

Activation of the mitogen-activated protein kinase (MAPK) pathway by the T-cell antigen receptor (TCR) in T cells involves a positive role for phosphatidylinositol 3-kinase (PI3K) activity. We recently reported that over-expression of the Syk protein tyrosine kinase in the Lck-negative JCaM1 cells enabled the TCR to induce a normal activation of the Erk2 MAPK and enhanced transcription of a reporter gene driven by the nuclear factor of activated T cells and AP-1. Because this system allows us to analyse the targets for Syk in receptor-mediated signalling, we examined the role of PI3K in signalling events between the TCR-regulated Syk and the downstream activation of Erk2. We report that inhibition of PI3K by wortmannin or an inhibitory p85 construct, p85deltaiSH2, reduced the TCR-induced Syk-dependent activation of Erk2, as well as the appearance of phospho-Erk and phospho-Mek. At the same time, expression of Syk resulted in the activation-dependent phosphorylation of three proteins that bound to the src homology 2 (SH2) domains of PI3K p85. The strongest of these bands had an apparent molecular mass of 36-38 kDa on SDS gels, and it was quantitatively removed from the lysates by adsorption to a fusion protein containing the SH2 domain of Grb2. The appearance of this band was Syk dependent, and it was seen only upon triggering of the TCR complex. Thus, p36/38 was phosphorylated by Syk or a Syk-regulated kinase, and this protein may provide a link to the recruitment and activation of PI3K, as well as to the Ras-MAPK pathway, in TCR-triggered T cells.

Adaptor Proteins, Signal Transducing↗

PubMed2003

MLH1p and MLH3p localize to precociously induced chiasmata of okadaic-acid-treated mouse spermatocytes.

With the phosphatase inhibitor, okadaic acid, we induce the precocious onset of the chiasmate stage and under those conditions show that the recombination nodules, MLH1 and MLH3 foci, are localized to the chiasmata. It is concluded that MLH1/3 foci are appropriate markers for the studies of crossovers/chiasmata development and distribution at late meiotic prophase.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Differential recruitment of p160 coactivators by glucocorticoid receptor between Schwann cells and astrocytes.

In the nervous system, glucocorticoids can exert beneficial or noxious effects, depending on their concentration and the duration of hormonal stimulation. They exert their effects on neuronal and glial cells by means of their cognate receptor, the glucocorticoid receptor (GR), which recruits the p160 coactivator family members SRC-1 (steroid receptor coactivator 1), SRC-2, and SRC-3 after hormone binding. In this study, we investigated the molecular pathways used by the GR in cultured glial cells of the central and the peripheral nervous systems, astrocytes and Schwann cells (MSC80 cells), respectively. We performed functional studies based on transient transfection of a minimal glucocorticoid-sensitive reporter gene into the glial cells to test the influence of overexpression or selective inhibition by short interfering RNA of the three p160 coactivator family members on GR transactivation. We demonstrate that, depending on the glial cell type, GR differentially recruits p160 family members: in Schwann cells, GR recruited SRC-1a, SRC-1e, or SRC-3, whereas in astrocytes, SRC-1e and SRC-2, and to a lesser extent SRC-3, were active toward GR signaling. The C-terminal nuclear receptor-interacting domain of SRC-1a participates in its exclusion from the GR transcriptional complex in astrocytes. Immunolocalization experiments revealed a cell-specific intracellular distribution of the p160s, which was dependent on the duration of the hormonal induction. For example, within astrocytes, SRC-1 and SRC-2 were mainly nuclear, whereas SRC-3 unexpectedly localized to the lumen of the Golgi apparatus. In contrast, in Schwann cells, SRC-1 showed a nucleocytoplasmic shuttling depending on hormonal stimulation, whereas SRC-2 remained strictly nuclear and SRC-3 remained predominantly cytoplasmic. Altogether, these results highlight the cell specificity and the time dependence of p160s recruitment by the activated GR in glial cells, revealing the complexity of GR-p160 assembly in the nervous system.

Adaptor Proteins, Signal Transducing↗

PubMed1999

NS5A, a nonstructural protein of hepatitis C virus, binds growth factor receptor-bound protein 2 adaptor protein in a Src homology 3 domain/ligand-dependent manner and perturbs mitogenic signaling.

Although hepatitis C virus (HCV) infection is an emerging global epidemic causing severe liver disorders, the molecular mechanisms of HCV pathogenesis remain elusive. The NS5A nonstructural protein of HCV contains several proline-rich sequences consistent with Src homology (SH) 3-binding sites found in cellular signaling molecules. Here, we demonstrate that NS5A specifically bound to growth factor receptor-bound protein 2 (Grb2) adaptor protein. Immunoblot analysis of anti-Grb2 immune complexes derived from HeLa S3 cells infected with a recombinant vaccinia virus (VV) expressing NS5A revealed an interaction between NS5A and Grb2 in vivo. An inactivating point mutation in the N-terminal SH3 domain, but not in the C-terminal SH3 domain, of Grb2 displayed significant diminished binding to NS5A. However, the same mutation in both SH3 regions completely abrogated Grb2 binding to NS5A, implying that the two SH3 domains bind in cooperative fashion to NS5A. Further, mutational analysis of NS5A assigned the SH3-binding region to a proline-rich motif that is highly conserved among HCV genotypes. Importantly, phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) was inhibited in HeLa S3 cells infected with NS5A-expressing recombinant VV but not recombinant VV control. Additionally, HeLa cells stably expressing NS5A were refractory to ERK1/2 phosphorylation induced by exogenous epidermal growth factor. Moreover, the coupling of NS5A to Grb2 in these cells was induced by epidermal growth factor stimulation. Therefore, NS5A may function to perturb Grb2-mediated signaling pathways by selectively targeting the adaptor. These findings highlight a viral interceptor of cellular signaling with potential implications for HCV pathogenesis.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Functional specificity of the mammalian Beclin-Vps34 PI 3-kinase complex in macroautophagy versus endocytosis and lysosomal enzyme trafficking.

Beclin 1 was originally identified as a novel Bcl-2-interacting protein, but co-immunoprecipitation studies suggest that the major physiological partner for Beclin 1 is the mammalian class III phosphatidylinositol 3-kinase (PI 3-kinase) Vps34. Beclin 1 has been proposed to function as a tumor suppressor by promoting cellular macroautophagy, a process that is known to depend on Vps34. However, an alternative role for Beclin 1 in modulating normal Vps34-dependent protein trafficking pathways has not been ruled out. This possibility was examined in U-251 glioblastoma cells. Immunoprecipitates of endogenous Beclin 1 contained human Vps34 (hVps34), but not Bcl-2. Suppression of Beclin 1 expression by short interfering (si)RNA-mediated gene silencing blunted the autophagic response of the cells to nutrient deprivation or C2-ceramide. However, other PI 3-kinase-dependent trafficking pathways, such as the post-endocytic sorting of the epidermal growth factor receptor (EGFR) or the proteolytic processing of procathepsin D en route from the trans-Golgi network (TGN) to lysosomes, were not affected. Depletion of Beclin 1 did not reduce endocytic internalization of a fluid phase marker (horseradish peroxidase, HRP) or cause swelling of late endosomal compartments typically seen in cells where the function of hVps34 is impaired. These findings argue against a role for Beclin 1 as an essential chaperone or adaptor for hVps34 in normal vesicular trafficking, and they support the hypothesis that Beclin 1 functions mainly to engage hVps34 in the autophagic pathway.

Animals↗

PubMed2006

Arf1p, Chs5p and the ChAPs are required for export of specialized cargo from the Golgi.

In Saccharomyces cerevisiae, the synthesis of chitin is temporally and spatially regulated through the transport of Chs3p (chitin synthase III) to the plasma membrane in the bud neck region. Traffic of Chs3p from the trans-Golgi network (TGN)/early endosome to the plasma membrane requires the function of Chs5p and Chs6p. Chs6p belongs to a family of four proteins that we have named ChAPs for Chs5p-Arf1p-binding Proteins. Here, we show that all ChAPs physically interact not only with Chs5p but also with the small GTPase Arf1p. A short sequence at the C-terminus of the ChAPs is required for protein function and the ability to bind to Chs5p. Simultaneous disruption of two members, Deltabud7 and Deltabch1, phenocopies a Deltachs6 or Deltachs5 deletion with respect to Chs3p transport. Moreover, the ChAPs interact with each other and can form complexes. In addition, they are all at least partially localized to the TGN in a Chs5p-dependent manner. Most importantly, several ChAPs can interact physically with Chs3p. We propose that the ChAPs facilitate export of cargo out of the Golgi.

ADP-Ribosylation Factor 1↗

PubMed2005

Sorting of major cargo glycoproteins into clathrin-coated vesicles.

The AP-1 and AP-2 complexes are the most abundant adaptors in clathrin-coated vesicles (CCVs), but clathrin-mediated trafficking can still occur in the absence of any detectable AP-1 or AP-2. To find out whether adaptor abundance reflects cargo abundance, we used lectin pulldowns to identify the major membrane glycoproteins in CCVs from human placenta and rat liver. Both preparations contained three prominent high molecular-weight proteins: the cation-independent mannose 6-phosphate receptor (CIMPR), carboxypeptidase D (CPD) and low-density lipoprotein receptor-related protein 1 (LRP1). To investigate how these proteins are sorted, we constructed and stably transfected CD8 chimeras into HeLa cells. CD8-CIMPR localized mainly to early/tubular endosomes, CD8-CPD to the trans Golgi network and CD8-LRP1 to late/multivesicular endosomes. All three constructs redistributed to the plasma membrane when clathrin was depleted by siRNA. CD8-CIMPR was also strongly affected by AP-2 depletion. CD8-CPD was moderately affected by AP-2 depletion but strongly affected by depleting AP-1 and AP-2 together. CD8-LRP1 was only slightly affected by AP-2 depletion; however, mutating an NPXY motif in the LRP1 tail caused it to become AP-2 dependent. These results indicate that all three proteins have AP-dependent sorting signals, which may help to explain the relative abundance of AP complexes in CCVs. However, the relatively low abundance of cargo proteins in CCV preparations suggests either that some of the APs may be empty or that the preparations may be dominated by empty coats.

Amino Acid Sequence↗

PubMed2006

G1/S Cyclins interact with regulatory subunit of PKA via A-kinase anchoring protein, AKAP95.

The mechanisms by which cyclins promote mammalian cell cycle progression have been a topic of intense investigation over the last decade. We previously described an interaction between D-type cyclins and A-kinase anchoring protein, AKAP95. Here, we demonstrate that AKAP95 can also bind cyclin E1. Association between AKAP95 and cyclins is displaced by CDKs. We show that these G(1)/S cyclins can interact with RII subunit of PKAalpha through AKAP95. The presence of alternate complexes cyclin-CDK and cyclin D/E-AKAP95-PKA.RIIalpha suggest different roles of G(1)/S cyclins and a wider biological importance of these interactions in cells.

A Kinase Anchor Proteins↗

PubMed1999

Possible involvement of a novel STAM-associated molecule "AMSH" in intracellular signal transduction mediated by cytokines.

STAM containing an SH3 (Src homology 3) domain and an immunoreceptor tyrosine-based activation motif was previously revealed to be implicated in signaling pathways immediately downstream of Jak2 and Jak3 tyrosine kinases associated with cytokine receptors. We molecularly cloned a novel molecule interacting with the SH3 domain of STAM, which was named AMSH (associated molecule with the SH3 domain of STAM). AMSH contains a putative bipartite nuclear localization signal and a homologous region of a c-Jun activation domain-binding protein 1 (JAB1) subdomain in addition to a binding site for the SH3 domain of STAM. AMSH mutant deleted of the C-terminal half conferred dominant negative effects on signaling for DNA synthesis and c-myc induction mediated by interleukin 2 and granulocyte macrophage-colony-stimulating factor. These results suggest that AMSH plays a critical role in the cytokine-mediated intracellular signal transduction downstream of the Jak2/Jak3.STAM complex.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Inhibition of stress-inducible kinase pathways by tumorigenic mutant p53.

More than 50% of human cancers contain p53 gene mutations and as a result accumulate altered forms of the full-length p53 protein. Although certain tumor types expressing mutant p53 protein have a poor prognostic process, the precise role of mutant p53 protein in highly malignant tumor cells is not well defined. Some p53 mutants, but not wild-type p53, are shown here to interact with Daxx, a Fas-binding protein that activates stress-inducible kinase pathways. Interaction of Daxx with p53 is highly dependent upon the specific mutation of p53. Tumorigenic mutants of p53 bind to Daxx and inhibit Daxx-dependent activation of the apoptosis signal-regulating kinase 1 stress-inducible kinases and Jun NH(2)-terminal kinase. Mutant p53 forms complexes with Daxx in cells, and consequently, mutant p53 is able to rescue cells from Daxx-dependent inhibition of proliferation. Thus, the accumulation of mutant p53 in tumor cells may contribute to tumorigenesis by inhibiting stress-inducible kinase pathways.

Adaptor Proteins, Signal Transducing↗