Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P50502 (Hip)
 7,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ligand-induced trafficking of chemokine receptors plays a significant role in the regulation of inflammatory processes and human immunodeficiency infection. Although many chemokine receptors have been demonstrated to internalize through clathrin-coated vesicles, a process that involves the binding of arrestins to the receptors, accumulating evidence has suggested the possible existence of other regulators. In a yeast two-hybrid screening using the C-terminal domain of CXCR2 as a bait, the Hsc70-interacting protein (Hip) was identified to interact with CXCR2. Hip binds CXCR2 through its C-terminal domain binding to the C-terminal leucine-rich domain (KILAIHGLI) of CXCR2. Hip associates with CXCR2 or CXCR4 in intact cells, and agonist stimulation increases the association. Mutation of the Ile-Leu motif in the C-terminal domain of CXCR2 blocks the agonist-dependent association of the mutant receptor with Hip. Overexpression of a tetratricopeptide repeat (TPR) deletion mutant form of Hip (Delta TPR), which is unable to bind Hsc70 (Prapapanich, V., Chen, S., Nair, S. C., Rimerman, R. A., and Smith, D. F. (1996) Mol. Endocrinol. 10, 420-431), but retains the ability to bind CXCR2, does not affect CXCR2-mediated mitogen-activated protein kinase activation. However, overexpression of Delta TPR significantly attenuates the agonist-induced internalization of CXCR2 and CXCR4 and attenuates CXCR2-mediated chemotaxis. These findings open the possibility for regulation of chemokine receptor signaling and trafficking by protein chaperone molecules.
 ...
PMID:Hsc/Hsp70 interacting protein (hip) associates with CXCR2 and regulates the receptor signaling and trafficking. 1175 89

Heat shock protein 90 (Hsp90) is a molecular chaperone involved in the folding and assembly of a limited set of "client" proteins, many of which are involved in signal transduction pathways. In vivo, it is found in complex with additional proteins, including the chaperones Hsp70, Hsp40, Hip and Hop (Hsp-interacting and Hsp-organising proteins, respectively), as well as high molecular mass immunophilins, such as FKBP59, and the small acidic protein p23. The role of these proteins in Hsp90-mediated assembly processes is poorly understood. It is known that ATP binding and hydrolysis are essential for Hsp90 function in vivo and in vitro. Here we show, for the first time, that human Hsp90 has ATPase activity in vitro. The ATPase activity is characterised using a sensitive assay based on a chemically modified form of the phosphate-binding protein from Escherichia coli. Human Hsp90 is a very weak ATPase, its activity is significantly lower than that of the yeast homologue, and it has a half-life of ATP hydrolysis of eight minutes at 37 degrees C. Using a physiological substrate of Hsp90, the ligand-binding domain of the glucocorticoid receptor, we show that this "client" protein can stimulate the ATPase activity up to 200-fold. This effect is highly specific and unfolded or partially folded proteins, which are known to bind to Hsp90, do not affect the ATPase activity. In addition, the peroxisome proliferator-activated receptor, which is related in both sequence and structure to the glucocorticoid receptor but which does not bind Hsp90, has no observable effect on the ATPase activity. We establish the effect of the co-chaperones Hop, FKBP59 and p23 on the basal ATPase activity as well as the client protein-stimulated ATPase activity of human Hsp90. In contrast with the yeast system, human Hop has little effect on the basal rate of ATP hydrolysis but significantly inhibits the client-protein stimulated rate. Similarly, FKBP59 has little effect on the basal rate but stimulates the client-protein stimulated rate further. In contrast, p23 inhibits both the basal and stimulated rates of ATP hydrolysis. Our results show that the ATPase activity of human Hsp90 is highly regulated by both client protein and co-chaperone binding. We suggest that the rate of ATP hydrolysis is critical to the mode of action of Hsp90, consistent with results that have shown that both over and under-active ATPase mutants of yeast Hsp90 have impaired function in vivo. We suggest that the tight regulation of the ATPase activity of Hsp90 is important and allows the client protein to remain bound to Hsp90 for sufficient time for activation to occur.
J Mol Biol 2002 Jan 25
PMID:Stimulation of the weak ATPase activity of human hsp90 by a client protein. 1181 47

Hip arthroplasty is a common surgical procedure, but the diagnosis of infection associated with hip arthroplasty remains challenging. Fluorine-18 fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has been shown to be a promising imaging modality in settings where infection is suspected. However, inflammatory reaction to surgery can result in increased FDG uptake at various anatomic locations, which may erroneously be interpreted as sites of infection. The purpose of this study was to assess the patterns and time course of FDG accumulation following total hip replacement over an extended period of time. Firstly, in a prospective study nine patients with total hip replacement were investigated to determine the patterns of FDG uptake over time. Three FDG-PET scans were performed in each patient at about 3, 6 and 12 months post arthroplasty. Secondly, in a retrospective analysis, the medical and surgical history and FDG-PET imaging results of 710 patients who had undergone whole-body scans for the evaluation of possible malignant disorders were reviewed. The history of arthroplasty and FDG-PET findings in the hip region were reviewed for this study. Patients with symptomatic arthroplasties or related complaints during FDG-PET scanning were excluded from the analysis. During the entire study period, all nine patients enrolled in the prospective study were demonstrated to have increased FDG uptake around the femoral head or neck portion of the prosthesis that extended to the soft tissues surrounding the femur. Among the patients reviewed in the retrospective study, 18 patients with a history of 21 hip arthroplasties who were asymptomatic at the time of FDG-PET scan met the criteria for inclusion. The time interval between the hip arthroplasty and the FDG-PET study ranged from 3 months to 288 months (mean+/-SD: 80.4+/-86.2 months). In 81% (17 of 21) of these prostheses, increased FDG uptake could be noted around the femoral head or neck portion of the prosthesis. The average time interval between arthroplasty and FDG-PET scan in these patients was 71.3 months. In only four prostheses (19%, 4 of 21) was no abnormally increased FDG uptake seen around the prostheses or adjacent sites. The average time interval in these patients was 114.8 months. It is concluded that following hip arthroplasty, non-specifically increased FDG uptake around the head or neck of the prosthesis persists for many years, even in patients without any complications. Therefore, to minimize the number of false-positive results for infection with PET studies obtained to evaluate a painful hip prosthesis, caution should be exercised when interpreting FDG uptake around the head or neck portion of the prosthesis.
Eur J Nucl Med Mol Imaging 2002 Oct
PMID:Persistent non-specific FDG uptake on PET imaging following hip arthroplasty. 1227 15

The anatomy and functions of muscle-tendon complexes and their bony attachments in birds and their outgroups show how the major pelvic limb muscle groups evolved. Fossils reveal that most changes evolved after the divergence of archosaurs in the Triassic, particularly in the dinosaurian precursors to birds. Three-dimensional limb control became concentrated at the hip joint; more distal joints and muscles were restricted to flexion or extension early in dinosaur evolution. Hip extensors expanded even though the primary femoral retractor M. caudofemoralis longus was reduced. Hip flexors and two-joint "hamstring" muscles were simplified to a few large heads. Knee extensors increased their sizes and moment arms early in bipedal dinosaurs, but the patella and cranial cnemial crest evolved later in birds. Lower limb muscles expanded as ossifications such as the hypotarsus increased their moment arms. The ossification of lower limb tendons, particularly in extensors, is a recent novelty of birds. Muscles and tendons that develop large forces, stresses, and moments to stabilize or move the limbs became increasingly prominent on the line to birds. Locomotion evolved in a stepwise pattern that only recently produced the derived limb control mechanisms of crown-group birds, such as the strongly flexed hip and knee joints.
Comp Biochem Physiol A Mol Integr Physiol 2002 Dec
PMID:The evolution of hindlimb tendons and muscles on the line to crown-group birds. 1248 92

The ubiquitin/proteasome system has been proposed to play an important role in Alzheimer's disease (AD) pathogenesis. However, the critical factor(s) modulating both amyloid-beta peptide (Abeta) neurotoxicity and ubiquitin/proteasome system in AD are not known. We report the isolation of an unusual ubiquitin-conjugating enzyme, E2-25K/Hip-2, as a mediator of Abeta toxicity. The expression of E2-25K/Hip-2 was upregulated in the neurons exposed to Abeta(1-42) in vivo and in culture. Enzymatic activity of E2-25K/Hip-2 was required for both Abeta(1-42) neurotoxicity and inhibition of proteasome activity. E2-25K/Hip-2 functioned upstream of apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK) in Abeta(1-42) toxicity. Further, the ubiquitin mutant, UBB+1, a potent inhibitor of the proteasome which is found in Alzheimer's brains, was colocalized and functionally interacted with E2-25K/Hip-2 in mediating neurotoxicity. These results suggest that E2-25K/Hip-2 is a crucial factor in regulating Abeta neurotoxicity and could play a role in the pathogenesis of Alzheimer's disease.
Mol Cell 2003 Sep
PMID:Essential role of E2-25K/Hip-2 in mediating amyloid-beta neurotoxicity. 1452 3

Here, we have used a chimera of green fluorescent protein (GFP) and the glucocorticoid receptor (GR) to study retrograde movement of a model soluble (i.e., non-vesicle-associated) protein in axons and dendrites of cultured NT2-N neurons. It is known that in non-neuronal cells, the GFP-GR moves from cytoplasm to the nucleus in a steroid-dependent manner by a rapid, hsp90-dependent mechanism. When rapid movement is inhibited by geldanamycin (GA), a specific inhibitor of the protein chaperone hsp90, the GFP-GR translocates slowly to the nucleus by diffusion. Here we show that GFP-GR expressed in hormone-free neurons is localized in both cytoplasm and neurites, and upon treatment with dexamethasone (DEX), it moves to the nucleus. In neurites, movement by diffusion is not possible, and we show that movement of the GFP-GR from neurites is blocked by geldanamycin, suggesting that the hsp90-dependent movement machinery is required for retrograde movement. In cells treated with both dexamethasone and geldanamycin, the GFP-GR becomes concentrated in fluorescent globules located periodically along the neurites. Carboxyl terminus of Hsc70-interacting protein (CHIP), the E3 ubiquitin ligase for the GR, also concentrates in the same loci in a steroid-dependent and geldanamycin-dependent manner. If geldanamycin is removed, the GFP-GR exits the globules and continues its retrograde movement. However, in the continued presence of geldanamycin, the GFP-GR in the globules undergoes proteasomal degradation, suggesting that the globules function as degradasomes. This is the first evidence for a linkage between receptor trafficking along neurites and receptor degradation by the proteasome.
Brain Res Mol Brain Res 2004 Apr 07
PMID:Retrograde transport of the glucocorticoid receptor in neurites requires dynamic assembly of complexes with the protein chaperone hsp90 and is linked to the CHIP component of the machinery for proteasomal degradation. 1504 63

Multiple molecular chaperones interact with steroid receptors to promote functional maturation and stability of receptor complexes. The heat shock protein (Hsp)70 cochaperone Hip has been identified in conjunction with Hsp70, Hsp90, and the Hsp70/Hsp90 cochaperone Hop/Sti1p in receptor complexes during an intermediate stage of receptor assembly, but a functional requirement for Hip in the receptor assembly process has not been established. Because the budding yeast Saccharomyces cerevisiae contains orthologs for most of the receptor-associated chaperones yet lacks an orthologous Hip gene, we exploited the well-established yeast model for steroid receptor function to ask whether Hip can alter steroid receptor function in vivo. Introducing human Hip into yeast enhances hormone-dependent activation of a reporter gene by glucocorticoid receptor (GR). Because Hip does not similarly enhance signaling by mineralocorticoid, progesterone, or estrogen receptors, a general effect on transcription can be excluded. Instead, Hip promotes functional maturation of GR without increasing steady-state levels of GR protein. Unexpectedly, Hip binding to Hsp70 is not critical for boosting GR responsiveness to hormone. In conclusion, Hip functions by a previously unrecognized mechanism to promote the efficiency of GR maturation in cells.
Mol Endocrinol 2004 Jul
PMID:The heat shock protein 70 cochaperone hip enhances functional maturation of glucocorticoid receptor. 1507 Oct 92

E2A transcription factors, E12 and E47, are important regulators of lymphocyte development. Notch signaling pathways have been shown to regulate E2A function by accelerating the degradation of E2A proteins through a mitogen-activated protein kinase-dependent and ubiquitin-mediated pathway. To further understand the mechanism underlying E2A ubiquitination and degradation, we conducted a yeast two-hybrid screen and identified the carboxyl terminus of Hsc70-interacting protein (CHIP) as an E47 binding protein. Here, we show that CHIP associates with E2A proteins in vivo and that overexpression of CHIP induces E47 degradation in a phosphorylation-dependent manner. Conversely, knocking down CHIP with small interfering RNA alleviates Notch-induced E47 degradation. CHIP binds E47 through the E protein homology domains 2 and 3 (EHD2 and EHD3). This interaction between CHIP and E47 is independent of the U-box domain with E3 ubiquitin ligase activity but requires the chaperone binding tetratricopeptide repeats domain. The ability of CHIP to induce E47 ubiquitination and degradation correlates with its ability to bind E47. We propose that CHIP, together with its partner Hsc70, forms a preubiquitination complex (PUC) with E47 and Skp2, thus facilitating the interaction between E47 and Skp2. CHIP also associates with Cul1, which introduces PUC to the SCF E3 ligase complex, responsible for E47 ubiquitination. Therefore, CHIP plays a crucial role in the ubiquitination and degradation of E2A proteins.
Mol Cell Biol 2004 Oct
PMID:Notch-induced E2A degradation requires CHIP and Hsc70 as novel facilitators of ubiquitination. 1545 69

Ubiquitin-positive deposits are histopathologically found in patients with Alzheimer's disease (AD). It is not understood why ubiquitin is accumulated in intra- and extra-cellular deposits or how it is involved in AD pathogenesis. Interestingly, recent evidence, including studies of E2-25K/Hip-2, has elucidated the molecular mechanism of the ubiquitin-proteasome system (UPS) malfunction in AD. The neurotoxicity and proteasome inhibition by Abeta, a main cause of AD pathogenesis, are mediated by increased E2-25K/Hip-2 in the brains of patients with AD. Furthermore, E2-25K/Hip-2 is required for the neurotoxicity that is mediated by a ubiquitin B mutant (UBB+1), which is a potent inhibitor of proteasomes that is found in patients with AD. Intensive research is required to identify the components of the UPS that are involved in AD pathogenesis.
Trends Mol Med 2004 Nov
PMID:Alzheimer's disease meets the ubiquitin-proteasome system. 1551 83

In estrogen target cells, estrogen receptor-alpha (ERalpha) protein levels are strictly regulated. Although receptor turnover is a continuous process, dynamic fluctuations in receptor levels, mediated primarily by the ubiquitin-proteasome pathway, occur in response to changing cellular conditions. In the absence of ligand, ERalpha is sequestered within a stable chaperone protein complex consisting of heat shock protein 90 (Hsp90) and cochaperones. However, the molecular mechanism(s) regulating ERalpha stability and turnover remain undefined. One potential mechanism involves CHIP, the carboxyl terminus of Hsc70-interacting protein, previously shown to target Hsp90-interacting proteins for ubiquitination and proteasomal degradation. In the present study, a role for CHIP in ERalpha protein degradation was investigated. In ER-negative HeLa cells transfected with ERalpha and CHIP, ERalpha proteasomal degradation increased, whereas ERalpha-mediated gene transcription decreased. In contrast, CHIP depletion by small interference RNA resulted in increased ERalpha accumulation and reporter gene transactivation. Transfection of mutant CHIP constructs demonstrated that both the U-box (containing ubiquitin ligase activity) and the tetratricopeptide repeat (TPR, essential for chaperone binding) domains within CHIP are required for CHIP-mediated ERalpha down-regulation. In addition, coimmunoprecipitation assays demonstrated that ERalpha and CHIP associate through the CHIP TPR domain. In ERalpha-positive breast cancer MCF7 cells, CHIP overexpression resulted in decreased levels of endogenous ERalpha protein and attenuation of ERalpha-mediated gene expression. Furthermore, the ERalpha-CHIP interaction was stimulated by the Hsp90 inhibitor geldanamycin (GA), resulting in enhanced ERalpha degradation; this GA effect was further augmented by CHIP overexpression but was abolished by CHIP depletion. Finally, ERalpha dissociation from CHIP by various ERalpha ligands, including 17beta-estradiol, 4-hydroxytamoxifen, and ICI 182,780, interrupted CHIP-mediated ERalpha degradation. These results demonstrate a role for CHIP in both basal and GA-induced ERalpha degradation. Furthermore, based on our observations that CHIP promotes ERalpha degradation and attenuates receptor-mediated gene transcription, we suggest that CHIP, by modulating ERalpha stability, contributes to the regulation of functional receptor levels, and thus hormone responsiveness, in estrogen target cells.
Mol Endocrinol 2005 Dec
PMID:CHIP (carboxyl terminus of Hsc70-interacting protein) promotes basal and geldanamycin-induced degradation of estrogen receptor-alpha. 1603 32


<< Previous 1 2 3 4 5 Next >>