Alternative titles; symbols
HGNC Approved Gene Symbol: RACK1
Cytogenetic location: 5q35.3 Genomic coordinates (GRCh38): 5:181,236,897-181,243,906 (from NCBI)
Using a chicken Gnb2 (139390)-like cDNA to probe a human B-lymphoblastoid cell line cDNA library, Guillemot et al. (1989) cloned GNB2L1. The deduced 317-amino acid protein shares significant similarity with GNB2, including an identical structure of 7 homologous segments and a number of identical or isofunctional consensus residues. Northern blot analysis detected a 1.3-kb transcript abundantly expressed in B-lymphoblastoid cells.
Activation of protein kinase C (e.g., PRKCA; 176960) is associated with its translocation from the cytosolic (soluble) fraction to the particulate (membrane) fraction. Pretreatment of membranes with proteases abolishes binding of protein kinase C, and several activated protein kinase C isozymes are localized on cytoskeletal structures, rather than on membranes. These data suggest that proteins anchor activated PKC at the site of translocation. Proteins were identified in the particulate fraction of heart and brain that bound activated PKC in a specific and saturable manner. These proteins were termed RACKs (for 'receptors for activated C-kinase'). Ron et al. (1994) cloned a cDNA encoding GNB2L1, which they referred to as RACK1. They found that the 36-kD RACK1 protein is a homolog of the beta subunit of G proteins, which are implicated in membrane anchorage of beta-adrenergic receptor kinase (109635, 109636) (Pitcher et al., 1992). Ron et al. (1994) interpreted the data as indicating a role for RACK1 in PRKC-mediated signaling.
Using the cytoplasmic domain of type I interferon receptor-2 (IFNAR2; 602376) as bait in a yeast 2-hybrid screen of a B-cell cDNA library, followed by confirmation in pull-down and coimmunoprecipitation experiments, Croze et al. (2000) captured clones encoding the C-terminal 216 amino acids of RACK1. This region of RACK1 excluded 2 N-terminal WD repeats as binding sites for IFNAR2. The minimum binding site on IFNAR2 mapped to residues 300-346. Immunofluorescence microscopy demonstrated that RACK1 was detectable throughout the cytoplasm before interferon beta-1 (147640) stimulation. After IFNB stimulation RACK1 expression was more intense and focused in the perinuclear area.
Ceci et al. (2003) demonstrated that the ribosomal 60S subunit is activated by release of eukaryotic translation initiation factor-6 (EIF6; 602912). In the cytoplasm, EIF6 is bound to free 60S but not to 80S subunits. Furthermore, EIF6 interacts in the cytoplasm with RACK1, a receptor for activated PKC. RACK1 is a major component of translating ribosomes, which harbor significant amounts of PKC. Loading 60S subunits with EIF6 caused a dose-dependent translational block and impairment of 80S formation, which were reversed by expression of RACK1 and stimulation of PKC in vivo and in vitro. PKC stimulation led to EIF6 phosphorylation, and mutation of a serine residue in the carboxy terminus of EIF6 impaired RACK1/PKC-mediated translational rescue. Ceci et al. (2003) proposed that EIF6 release regulates subunit joining, and that RACK1 provides a physical and functional link between PKC signaling and ribosome activation.
Patterson et al. (2004) determined that RACK1 bound inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) receptors in several mammalian cell lines and regulated Ca(2+) release by enhancing receptor binding affinity for Ins(1,4,5)P3. Overexpression of RACK1 or depletion of RACK1 by interference RNA augmented or diminished Ca(2+) release, respectively, without affecting Ca(2+) entry. Patterson et al. (2004) concluded that RACK1 is a mediator of agonist-induced Ca(2+) release.
Gerbasi et al. (2004) presented evidence that mammalian RACK1 and a yeast homolog, Asc1, are conserved core components of eukaryotic ribosomes. They concluded that one function of RACK1 or Asc1 is to repress gene expression.
Liu et al. (2007) showed that RACK1 interacted with the hypoxia-induced factor HIF1A (603348) and promoted its proteasomal degradation through an oxygen-independent pathway. RACK1 competed with the HIF1A-stabilizing protein HSP90 (HSPCA; 140571) for HIF1A binding in vitro and in human cells, and RACK1 linked HIF1A to elongin C (TCEB1; 600788), promoting ubiquitination of HIF1A. Liu et al. (2007) concluded that RACK1 is an essential component of an oxygen-independent mechanism for regulating HIF1A stability.
Robles et al. (2010) analyzed mouse protein complexes containing BMAL1 (602550) to gain insight into the mechanisms of circadian feedback. Receptors for RACK1 and protein kinase C-alpha (176960) were recruited in a circadian manner into a nuclear BMAL1 complex during the negative feedback phase of the cycle. Overexpression of RACK1 and PKC-alpha suppressed CLOCK (601851)-BMAL1 transcriptional activity, and RACK1 stimulated phosphorylation of BMAL1 by PKC-alpha in vitro. Depletion of endogenous RACK1 or PKC-alpha from fibroblasts shortened the circadian period, demonstrating that both molecules function in the clock oscillatory mechanism. Robles et al. (2010) concluded that the classical PKC signaling pathway is not limited to relaying external stimuli but is rhythmically activated by internal processes, forming an integral part of the circadian feedback loop.
Majzoub et al. (2014) screened Drosophila ribosomal proteins to determine their impact on cellular viability and promotion of Dicistroviridae (DCV) virus replication. They found that knockdown of Rack1 did not affect cell viability, but that it resulted in a reduction of the DCV titer. Unlike DCV, which is dependent on an internal ribosome entry site (IRES) for translation, viruses that use cap-dependent initiation of translation were unaffected by knockdown of Rack1. Majzoub et al. (2014) found that silencing RACK1 in a human hepatocarcinoma cell line significantly impaired infection with hepatitis C virus (HCV; see 609532), which is dependent on an IRES, at a level comparable to those observed with silencing of the HCV host factors CD81 (186845) or CYPA (PPIA; 123840). Silencing of RACK1 did not affect liver cell proliferation or viability, in contrast with silencing of the ribosomal protein RPS3 (600454). The authors found that RACK1 and MIR122 (609582) regulated HCV by different mechanisms, and further mechanistic analyses suggested the involvement of EIF3J (603910) with HCV translation mediated by RACK1. Majzoub et al. (2014) concluded that RACK1 is involved in IRES-mediated translation of viruses, but that it is not required for cell viability.
Jha et al. (2017) reported that a poxvirus kinase phosphorylates serine/threonine residues in the human RACK1 that are not phosphorylated in uninfected cells or cells infected by other viruses. These modified residues cluster in an extended loop in RACK1, phosphorylation of which selects for translation of viral or reporter mRNAs with 5-prime untranslated regions that contain adenosine repeats, so-called polyA-leaders. Structural and phylogenetic analyses revealed that although RACK1 is highly conserved, this loop is variable and contains negatively charged amino acids in plants, in which these leaders act as translational enhancers. Phosphomimetics and interspecies chimeras showed that negative charge in the RACK1 loop dictates ribosome selectivity towards viral RNAs. By converting human RACK1 to a charged, plant-like state, poxviruses remodeled host ribosomes so that adenosine repeats erroneously generated by slippage of the viral RNA polymerase confer a translational advantage. Jha et al. (2017) concluded that their findings provided insight into ribosome customization through trans-kingdom mimicry and the mechanics of species-specific leader activity that underlie poxvirus polyA-leaders.
Gross (2015) mapped the RACK1 gene to chromosome 5q35.3 based on an alignment of the RACK1 sequence (GenBank AY336089) with the genomic sequence (GRCh38).
Ceci, M., Gaviraghi, C., Gorrini, C., Sala, L. A., Offenhauser, N., Marchisio, P. C., Biffo, S. Release of eIF6 (p27-BBP) from the 60S subunit allows 80S ribosome assembly. Nature 426: 579-584, 2003. [PubMed: 14654845] [Full Text: https://doi.org/10.1038/nature02160]
Croze, E., Usacheva, A., Asarnow, D., Minshall, R. D., Perez, H. D., Colamonici, O. Receptor for activated C-kinase (RACK-1), a WD motif-containing protein, specifically associates with the human type I IFN receptor. J. Immun. 165: 5127-5132, 2000. [PubMed: 11046044] [Full Text: https://doi.org/10.4049/jimmunol.165.9.5127]
Gerbasi, V. R., Weaver, C. M., Hill, S., Friedman, D. B., Link, A. J. Yeast Asc1p and mammalian RACK1 are functionally orthologous core 40S ribosomal proteins that repress gene expression. Molec. Cell. Biol. 24: 8276-8287, 2004. [PubMed: 15340087] [Full Text: https://doi.org/10.1128/MCB.24.18.8276-8287.2004]
Gross, M. B. Personal Communication. Baltimore, Md. 4/24/2015.
Guillemot, F., Billault, A., Auffray, C. Physical linkage of a guanine nucleotide-binding protein-related gene to the chicken major histocompatibility complex. Proc. Nat. Acad. Sci. 86: 4594-4598, 1989. [PubMed: 2499885] [Full Text: https://doi.org/10.1073/pnas.86.12.4594]
Jha, S., Rollins, M. G., Fuchs, G., Procter, D. J., Hall, E. A., Cozzolino, K., Sarnow, P., Savas, J. N., Walsh, D. Trans-kingdom mimicry underlies ribosome customization by a poxvirus kinase. Nature 546: 651-655, 2017. [PubMed: 28636603] [Full Text: https://doi.org/10.1038/nature22814]
Liu, Y. V., Baek, J. H., Zhang, H., Diez, R., Cole, R. N., Semenza, G. L. RACK1 competes with HSP90 for binding to HIF-1-alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1-alpha. Molec. Cell 25: 207-217, 2007. [PubMed: 17244529] [Full Text: https://doi.org/10.1016/j.molcel.2007.01.001]
Majzoub, K., Hafirassou, M. L., Meignin, C., Goto, A., Marzi, S., Fedorova, A., Verdier, Y., Vinh, J., Hoffmann, J. A., Martin, F., Baumert, T. F., Schuster, C., Imler, J.-L. RACK1 controls IRES-mediated translation of viruses. Cell 159: 1086-1095, 2014. [PubMed: 25416947] [Full Text: https://doi.org/10.1016/j.cell.2014.10.041]
Patterson, R. L., van Rossum, D. B., Barrow, R. K., Snyder, S. H. RACK1 binds to inositol 1,4,5-triphosphate receptors and mediates Ca(2+) release. Proc. Nat. Acad. Sci. 101: 2328-2332, 2004. [PubMed: 14983009] [Full Text: https://doi.org/10.1073/pnas.0308567100]
Pitcher, J. A., Inglese, L., Higgins, J. B., Arriza, J. L., Casey, P. J., Kim, C., Benovic, J. L., Kwatra, M. M., Caron, M. G., Lefkowitz, R. J. Role of beta-gamma subunits of G proteins in targeting the beta-adrenergic receptor kinase to membrane-bound receptors. Science 257: 1264-1267, 1992. [PubMed: 1325672] [Full Text: https://doi.org/10.1126/science.1325672]
Robles, M. S., Boyault, C., Knutti, D., Padmanabhan, K., Weitz, C. J. Identification of RACK1 and protein kinase C-alpha as integral components of the mammalian circadian clock. Science 327: 463-466, 2010. [PubMed: 20093473] [Full Text: https://doi.org/10.1126/science.1180067]
Ron, D., Chen, C.-H., Caldwell, J., Jamieson, L., Orr, E., Mochly-Rosen, D. Cloning of an intracellular receptor for protein kinase C: a homolog of the beta subunit of G proteins. Proc. Nat. Acad. Sci. 91: 839-843, 1994. Note: Erratum: Proc. Nat. Acad. Sci. 92: 2016 only, 1995. [PubMed: 8302854] [Full Text: https://doi.org/10.1073/pnas.91.3.839]