A variant of the PTPN22-encoded Lyp phosphatase (Lyp620W) confers risk for autoimmune disease, but the mechanisms underlying this association remain unclear. We show here that mice expressing the Lyp variant homolog Pep619W manifest thymic and splenic enlargement accompanied by increases in T-cell number, activation and positive selection and in dendritic- and B-cell activation. Although Ptpn22 (Pep) transcript levels were comparable in Pep619W and wild-type Pep619R mice, Pep protein levels were dramatically reduced in the mutant mice, with Pep619W protein being more rapidly degraded and showing greater association with and in vitro cleavage by calpain 1 than Pep619R. Similarly, levels of the Lyp620W variant were decreased in human T and B cells, and its calpain binding and cleavage were increased relative to wild-type Lyp620R. Thus, calpain-mediated degradation with consequently reduced Lyp/Pep expression and lymphocyte and dendritic cell hyperresponsiveness represents a mechanism whereby Lyp620W may increase risk for autoimmune disease.
The Hedgehog (Hh) signaling pathway has critical functions during embryogenesis of both invertebrate and vertebrate species [1]; defects in this pathway in humans can cause developmental disorders as well as neoplasia [2]. Although the Gli1, Gli2, and Gli3 zinc finger proteins are known to be effectors of Hh signaling in vertebrates, the mechanisms regulating activity of these transcription factors remain poorly understood [3] [4]. In Drosophila, activity of the Gli homolog Cubitus interruptus (Ci) is likely to be modulated by its interaction with a cytoplasmic complex containing several other proteins [5] [6], including Costal2, Fused (Fu), and Suppressor of fused (Su(fu)), the last of which has been shown to interact directly with Ci [7]. We have cloned mouse Suppressor of fused (mSu(fu)) and detected its 4.5 kb transcript throughout embryogenesis and in several adult tissues. In cultured cells, mSu(fu) overexpression inhibited transcriptional activation mediated by Sonic hedgehog (Shh), Gli1 and Gli2. Co-immunoprecipitation of epitope-tagged proteins indicated that mSu(fu) interacts with Gli1, Gli2, and Gli3, and that the inhibitory effects of mSu(fu) on Gli1's transcriptional activity were mediated through interactions with both amino- and carboxy-terminal regions of Gli1. Gli1 was localized primarily to the nucleus of both HeLa cells and the Shh-responsive cell line MNS-70; co-expression with mSu(fu) resulted in a striking increase in cytoplasmic Gli1 immunostaining. Our findings indicate that mSu(fu) can function as a negative regulator of Shh signaling and suggest that this effect is mediated by interaction with Gli transcription factors.
Sorting nexins (SNX) comprise a family of proteins with homology to several yeast proteins, including Vps5p and Mvp1p, that are required for the sorting of proteins to the yeast vacuole. Human SNX1, -2, and -4 have been proposed to play a role in receptor trafficking and have been shown to bind to several receptor tyrosine kinases, including receptors for epidermal growth factor, platelet-derived growth factor, and insulin as well as the long form of the leptin receptor, a glycoprotein 130-associated receptor. We now describe a novel member of this family, SNX6, which interacts with members of the transforming growth factor- family of receptor serine-threonine kinases. These receptors belong to two classes: type II receptors that bind ligand, and type I receptors that are subsequently recruited to transduce the signal. Of the type II receptors, SNX6 was found to interact strongly with ActRIIB and more moderately with wild type and kinase-defective mutants of TRII. Of the type I receptors, SNX6 was found to interact only with inactivated TRI. SNXs 1-4 also interacted with the transforming growth factor- receptor family, showing different receptor preferences. Conversely, SNX6 behaved similarly to the other SNX proteins in its interactions with receptor tyrosine kinases. Strong heteromeric interactions were also seen among SNX1, -2, -4, and -6, suggesting the formation in vivo of oligomeric complexes. These findings are the first evidence for the association of the SNX family of molecules with receptor serine-threonine kinases.The transforming growth factor- (TGF-) 1 family includes a large number of peptides, including the TGF-s themselves, activin/inhibin, the bone morphogenetic proteins (BMPs), the growth and differentiation factors (GDFs), glial-derived neurotrophic factor, and Mü llerian inhibitory substance (1). Although there are no yeast TGF-s, homologs have been identified in primitive metazoans, including Caenorhabditis elegans and Drosophila (2-4). With the exception of only glial-derived neurotrophic factor, these ligands signal through heterotetrameric pairs of serine-threonine kinase receptors. Ligand first interacts with a type II receptor, which, following ligand binding, recruits a type I receptor (5). The type II receptors are constitutively active kinases, catalyzing phosphorylation both of themselves in an autocatalytic reaction and of the recruited type I receptor (6). Once bound to ligand and phosphorylated by the type II receptor, the type I receptor then transduces the signal to the intracellular signaling intermediates, including the recently described family of Smad proteins (7-13). In general, one or two closely related type I and one or two closely related type II receptors are utilized by each class of ligand. For example, TGF-1 and TGF-3 bind to the type II TGF- receptor (TRII), with subsequent recruitment of the type I TGF- receptor (TRI/ALK5 (activin-like kinase 5)) (6). Similarly, activin binds to either ActRII or ActRIIB, with activin type IB receptor (ALK4) or possi...
Suppressor of fused (Su(fu)) is a negative regulator of the Hedgehog signaling pathway that controls the nuclear-cytoplasmic distribution of Gli/Ci transcription factors through direct protein-protein interactions. We show here that Su(fu) is present in a complex with the oncogenic transcriptional activator -catenin and functions as a negative regulator of T-cell factor (Tcf)-dependent transcription. Overexpression of Su(fu) in SW480 (APC mut ) colon cancer cells in which -catenin protein is stabilized leads to a reduction in nuclear -catenin levels and in Tcf-dependent transcription. This effect of Su(fu) overexpression can be blocked by treatment of these cells with leptomycin B, a specific inhibitor of CRM1-mediated nuclear export. Overexpression of Su(fu) suppresses growth of SW480 (APC mut ) tumor cells in nude mice. These observations indicate that Su(fu) negatively regulates -catenin signaling and that CRM-1-mediated nuclear export plays a role in this regulation. Our results also suggest that Su(fu) acts as a tumor suppressor.The oncogenic transcriptional activator -catenin is a major mediator in Wnt signaling (1-4). A large multiprotein complex that includes APC 1 and axin normally facilitates the phosphorylation of -catenin by GSK3. Phosphorylated -catenin binds to the F-box protein TrCP and is then modified by ubiquitination and subjected to proteasome-mediated protein degradation. When cells are exposed to the Wnt signal, -catenin phosphorylation and its subsequent ubiquitination are blocked. -Catenin is thus diverted from the proteasome; instead, -catenin accumulates and translocates to the nucleus, where it interacts with members of the Tcf/Lef family of transcription factors and activates transcription of Wnt-responsive genes. In tumors, -catenin degradation is blocked by mutations of APC, axin, or -catenin itself. As a result, stabilized -catenin enters the nucleus and -catenin⅐Tcf complexes activate oncogenic target genes.Nuclear translocation of -catenin is of key importance in its ability to regulate transcription, yet little is known about the factors important in controlling the nuclear versus cytoplasmic distribution of -catenin. -Catenin lacks a nuclear import signal, and it docks to the nuclear membrane by a mechanism that is Ran-independent and does not require importins (5). Nuclear import of -catenin is also independent of its association with the Tcf transcription factors because mutant forms of -catenin that do not bind Tcf proteins can enter the nucleus (6). Microinjection studies show that -catenin rapidly exits the nucleus, suggesting a role for nuclear export in the regulation of the intracellular distribution of -catenin (7).Several studies demonstrate that APC is a nucleo-cytoplasmic protein with export from the nucleus inhibited by LMB, a specific inhibitor of CRM1-mediated nuclear export (8 -10). CRM1, also called exportin-1, is an export karypopherin that binds to a leucine-rich nuclear export signal on its target protein and mediates nuclear-cytoplasm...
Unliganded thyroid hormone (TH) receptors (TRs) and other nuclear receptors (NRs) repress transcription of hormone-activated genes by recruiting corepressors (CoRs), such as NR CoR (N-CoR) and SMRT. Unliganded TRs also activate transcription of THrepressed genes. Some evidence suggests that these effects also involve TR͞CoR contacts; however, the precise reasons that CoRs activate transcription in these contexts are obscure. Unraveling these mechanisms is complicated by the fact that it is difficult to decipher direct vs. indirect effects of TR-coregulator contacts in mammalian cells. In this study, we used yeast, Saccharomyces cerevisiae, which lack endogenous NRs and NR coregulators, to determine how unliganded TRs can activate transcription. We previously showed that adenovirus 5 early-region 1A coactivates unliganded TRs in yeast, and that these effects are blocked by TH. We show here that human adenovirus type 5 early region 1A (
In mammalian cells, the human adenovirus type 5 early region 1A (E1A) oncoprotein functions as a thyroid hormone (TH)-dependent activator of the thyroid hormone receptor (TR). Interestingly, in the cellular context of the yeast Saccharomyces cerevisiae, E1A acts as a TR-specific constitutive coactivator that is down-regulated by TH. TH reduces the interaction of E1A with the TR in yeast but not HeLa cells. The N-terminal 82 amino acids of E1A are sufficient for coactivation in yeast and residues 4-29 are essential. In yeast, expression of the nuclear receptor corepressor (N-CoR) could down-regulate constitutive transcriptional activation of the TR by E1A, whereas expression of the glucocorticoid receptor interacting protein 1 (GRIP-1) coactivator reconstituted the E1A-induced pattern of enhanced TH-dependent gene activation by TR observed in mammalian cells. We further show that the mating type switching gene (SWI)/sucrose nonfermenting (SNF) gene chromatin remodeling complex is required for both TH/GRIP-1- and E1A-dependent coactivator function, whereas the general control nonrepressed protein (GCN5)/alteration/deficiency in activation protein (ADA2) components of the SPT, ADA, GCN5, acetylation (SAGA) transcriptional adaptor complex are required for TH/GRIP-1, but not E1A-dependent activation of the TR. Taken together, these studies demonstrate that the novel TR-specific coactivator function of E1A in yeast depends on the SWI/SNF chromatin remodeling complex and can be further influenced by changes in the cellular complement of transcriptional coregulatory proteins.
Background: The intracellular signaling events of the Bone Morphogenetic Proteins (BMPs) involve the R-Smad family members Smad1, Smad5, Smad8 and the Co-Smad, Smad4. Smads are currently considered to be DNA-binding transcriptional modulators and shown to recruit the master transcriptional co-activator CBP/p300 for transcriptional activation. SNIP1 is a recently discovered novel repressor of CBP/p300. Currently, the detailed molecular mechanisms that allow R-Smads and Co-Smad to co-operatively modulate transcription events are not fully understood.
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