Receptor for activated C kinase 1 explained

Receptor for activated C kinase 1 (RACK1), also known as guanine nucleotide-binding protein subunit beta-2-like 1 (GNB2L1), is a 35 kDa protein that in humans is encoded by the RACK1 gene.^{[1] [2]}

Function

RACK1 was originally isolated and identified as an intracellular protein receptor for protein kinase C, noting the significant homology to the beta subunit of heterotrimeric G proteins. Later studies established RACK1, and its yeast homolog Asc1, as a core ribosomal protein of the eukaryotic small (40S) ribosomal subunit.^{[3] [4] [5]} Much of the function of Asc1/RACK1 appears to result from its position on the 'head' of the 40S ribosomal subunit.^[6] Asc1/RACK1 participates in several aspects of eukaryotic translation and ribosome quality control, including IRES-mediated translation,^[7] non-stop decay,^[8] non-functional 18S ribosomal RNA decay,^[9] and frameshifting.^[10]

Interactions

RACK1 is positioned at the solvent-exposed surface of the 40S ribosomal subunit, where it is held in place through contacts with both the 18S rRNA and other ribosomal proteins, including uS3, uS9, and eS17. Additionally, RACK1 has been shown to interact with:

• AGTRAP^[11]
• Androgen receptor,^[12]
• CD18,^[13]
• CD29^{[13] [14]}
• Cyclin A1^[15]
• EIF6,^[16]
• FYN,^{[17] [18]}
• IFNAR2,^[19]
• Janus kinase 1
• OTUB1,^[20]
• P73,^[21]
• PDE4D,^{[22] [23]}
• PRKCB1,^[24]
• PRKCE,^[25]
• PTPRM,^{[26] [27]}
• RAS p21 protein activator 1,^[28]
• ST7,^[29]
• STAT1,^{[30] [31]}
• Src,^[32] and
• Tyrosine kinase 2.^[31]

See also

• Eukaryotic small ribosomal subunit (40S)
• Protein kinase C
• Heterotrimeric G protein

Further reading

• Liu YV, Semenza GL . RACK1 vs. HSP90: competition for HIF-1 alpha degradation vs. stabilization . Cell Cycle . 6 . 6 . 656–9 . March 2007 . 17361105 . 10.4161/cc.6.6.3981 . free .
• Mochly-Rosen D, Miller KG, Scheller RH, Khaner H, Lopez J, Smith BL . p65 fragments, homologous to the C2 region of protein kinase C, bind to the intracellular receptors for protein kinase C . Biochemistry . 31 . 35 . 8120–4 . September 1992 . 1326322 . 10.1021/bi00150a003 .
• Dawson SJ, White LA . Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin . The Journal of Infection . 24 . 3 . 317–20 . May 1992 . 1602151 . 10.1016/S0163-4453(05)80037-4 .
• Pumiglia KM, LeVine H, Haske T, Habib T, Jove R, Decker SJ . A direct interaction between G-protein beta gamma subunits and the Raf-1 protein kinase . The Journal of Biological Chemistry . 270 . 24 . 14251–4 . June 1995 . 7782277 . 10.1074/jbc.270.24.14251 . free .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Disatnik MH, Hernandez-Sotomayor SM, Jones G, Carpenter G, Mochly-Rosen D . Phospholipase C-gamma 1 binding to intracellular receptors for activated protein kinase C . Proceedings of the National Academy of Sciences of the United States of America . 91 . 2 . 559–63 . January 1994 . 8290562 . 42988 . 10.1073/pnas.91.2.559 . 1994PNAS...91..559D . free .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Liliental J, Chang DD . Rack1, a receptor for activated protein kinase C, interacts with integrin beta subunit . The Journal of Biological Chemistry . 273 . 4 . 2379–83 . January 1998 . 9442085 . 10.1074/jbc.273.4.2379 . free .
• Chang BY, Conroy KB, Machleder EM, Cartwright CA . RACK1, a receptor for activated C kinase and a homolog of the beta subunit of G proteins, inhibits activity of src tyrosine kinases and growth of NIH 3T3 cells . Molecular and Cellular Biology . 18 . 6 . 3245–56 . June 1998 . 9584165 . 108906 . 10.1128/mcb.18.6.3245 .
• Rietzler M, Bittner M, Kolanus W, Schuster A, Holzmann B . The human WD repeat protein WAIT-1 specifically interacts with the cytoplasmic tails of beta7-integrins . The Journal of Biological Chemistry . 273 . 42 . 27459–66 . October 1998 . 9765275 . 10.1074/jbc.273.42.27459 . free .
• Shimohama S, Kamiya S, Taniguchi T, Kimura J . Intracellular receptors for activated C-kinase in the postmortem human brain: no alteration in Alzheimer disease . Alzheimer Disease and Associated Disorders . 12 . 4 . 384–6 . December 1998 . 9876970 . 10.1097/00002093-199812000-00022 .
• Yarwood SJ, Steele MR, Scotland G, Houslay MD, Bolger GB . The RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform . The Journal of Biological Chemistry . 274 . 21 . 14909–17 . May 1999 . 10329691 . 10.1074/jbc.274.21.14909 . free .
• Ron D, Jiang Z, Yao L, Vagts A, Diamond I, Gordon A . Coordinated movement of RACK1 with activated betaIIPKC . The Journal of Biological Chemistry . 274 . 38 . 27039–46 . September 1999 . 10480917 . 10.1074/jbc.274.38.27039 . free .
• Geijsen N, Spaargaren M, Raaijmakers JA, Lammers JW, Koenderman L, Coffer PJ . Association of RACK1 and PKCbeta with the common beta-chain of the IL-5/IL-3/GM-CSF receptor . Oncogene . 18 . 36 . 5126–30 . September 1999 . 10490850 . 10.1038/sj.onc.1202896 . free .
• Smith PR, de Jesus O, Turner D, Hollyoake M, Karstegl CE, Griffin BE, Karran L, Wang Y, Hayward SD, Farrell PJ . Structure and coding content of CST (BART) family RNAs of Epstein-Barr virus . Journal of Virology . 74 . 7 . 3082–92 . April 2000 . 10708423 . 111807 . 10.1128/JVI.74.7.3082-3092.2000 .
• Ellis JH, Ashman C, Burden MN, Kilpatrick KE, Morse MA, Hamblin PA . GRID: a novel Grb-2-related adapter protein that interacts with the activated T cell costimulatory receptor CD28 . Journal of Immunology . 164 . 11 . 5805–14 . June 2000 . 10820259 . 10.4049/jimmunol.164.11.5805 . free .
• Croze E, Usacheva A, Asarnow D, Minshall RD, Perez HD, Colamonici O . Receptor for activated C-kinase (RACK-1), a WD motif-containing protein, specifically associates with the human type I IFN receptor . Journal of Immunology . 165 . 9 . 5127–32 . November 2000 . 11046044 . 10.4049/jimmunol.165.9.5127 . free .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .

Notes and References

1. Ron D, Chen CH, 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 . Proceedings of the National Academy of Sciences of the United States of America . 91 . 3 . 839–43 . February 1994 . 8302854 . 521407 . 10.1073/pnas.91.3.839 . 1994PNAS...91..839R . free .
2. Guillemot F, Billault A, Auffray C . Physical linkage of a guanine nucleotide-binding protein-related gene to the chicken major histocompatibility complex . Proceedings of the National Academy of Sciences of the United States of America . 86 . 12 . 4594–8 . June 1989 . 2499885 . 287317 . 10.1073/pnas.86.12.4594 . 1989PNAS...86.4594G . free .
3. Sengupta J, Nilsson J, Gursky R, Spahn CM, Nissen P, Frank J . Identification of the versatile scaffold protein RACK1 on the eukaryotic ribosome by cryo-EM . Nature Structural & Molecular Biology . 11 . 10 . 957–62 . October 2004 . 15334071 . 10.1038/nsmb822 . 20751757 .
4. Gerbasi VR, Weaver CM, Hill S, Friedman DB, Link AJ . Yeast Asc1p and mammalian RACK1 are functionally orthologous core 40S ribosomal proteins that repress gene expression . Molecular and Cellular Biology . 24 . 18 . 8276–87 . September 2004 . 15340087 . 10.1128/mcb.24.18.8276-8287.2004 . 515043.
5. Rabl J, Leibundgut M, Ataide SF, Haag A, Ban N . Crystal structure of the eukaryotic 40S ribosomal subunit in complex with initiation factor 1 . Science . 331 . 6018 . 730–6 . February 2011 . 21205638 . 10.1126/science.1198308 . 2011Sci...331..730R . 20.500.11850/153130 . 24771575 . free .
6. Coyle SM, Gilbert WV, Doudna JA . Direct link between RACK1 function and localization at the ribosome in vivo . Molecular and Cellular Biology . 29 . 6 . 1626–34 . March 2009 . 19114558 . 10.1128/mcb.01718-08 . 2648249.
7. Majzoub K, Hafirassou ML, Meignin C, Goto A, Marzi S, Fedorova A, Verdier Y, Vinh J, Hoffmann JA, Martin F, Baumert TF, Schuster C, Imler JL . RACK1 controls IRES-mediated translation of viruses . Cell . 159 . 5 . 1086–1095 . November 2014 . 25416947 . 10.1016/j.cell.2014.10.041 . 4243054.
8. Ikeuchi K, Inada T . Ribosome-associated Asc1/RACK1 is required for endonucleolytic cleavage induced by stalled ribosome at the 3' end of nonstop mRNA . Scientific Reports . 6 . 1 . 28234 . June 2016 . 27312062 . 10.1038/srep28234 . 4911565. 2016NatSR...628234I .
9. Limoncelli KA, Merrikh CN, Moore MJ . ASC1 and RPS3: new actors in 18S nonfunctional rRNA decay . RNA . 23 . 12 . 1946–1960 . December 2017 . 28956756 . 10.1261/rna.061671.117 . 5689013.
10. Wolf AS, Grayhack EJ . Asc1, homolog of human RACK1, prevents frameshifting in yeast by ribosomes stalled at CGA codon repeats . RNA . 21 . 5 . 935–45 . May 2015 . 25792604 . 10.1261/rna.049080.114 . 4408800.
11. Wang W, Huang Y, Zhou Z, Tang R, Zhao W, Zeng L, Xu M, Cheng C, Gu S, Ying K, Xie Y, Mao Y . Identification and characterization of AGTRAP, a human homolog of murine Angiotensin II Receptor-Associated Protein (Agtrap) . The International Journal of Biochemistry & Cell Biology . 34 . 1 . 93–102 . January 2002 . 11733189 . 10.1016/s1357-2725(01)00094-2 .
12. Rigas AC, Ozanne DM, Neal DE, Robson CN . The scaffolding protein RACK1 interacts with androgen receptor and promotes cross-talk through a protein kinase C signaling pathway . The Journal of Biological Chemistry . 278 . 46 . 46087–93 . November 2003 . 12958311 . 10.1074/jbc.M306219200 . free .
13. Liliental J, Chang DD . Rack1, a receptor for activated protein kinase C, interacts with integrin beta subunit . The Journal of Biological Chemistry . 273 . 4 . 2379–83 . January 1998 . 9442085 . 10.1074/jbc.273.4.2379 . free .
14. Lee HS, Millward-Sadler SJ, Wright MO, Nuki G, Al-Jamal R, Salter DM . Activation of Integrin-RACK1/PKCalpha signalling in human articular chondrocyte mechanotransduction . Osteoarthritis and Cartilage . 10 . 11 . 890–7 . November 2002 . 12435334 . 10.1053/joca.2002.0842 . free .
15. Diederichs S, Bäumer N, Ji P, Metzelder SK, Idos GE, Cauvet T, Wang W, Möller M, Pierschalski S, Gromoll J, Schrader MG, Koeffler HP, Berdel WE, Serve H, Müller-Tidow C . Identification of interaction partners and substrates of the cyclin A1-CDK2 complex . The Journal of Biological Chemistry . 279 . 32 . 33727–41 . August 2004 . 15159402 . 10.1074/jbc.M401708200 . free .
16. Ceci M, Gaviraghi C, Gorrini C, Sala LA, Offenhäuser N, Marchisio PC, Biffo S . Release of eIF6 (p27BBP) from the 60S subunit allows 80S ribosome assembly . Nature . 426 . 6966 . 579–84 . December 2003 . 14654845 . 10.1038/nature02160 . 2003Natur.426..579C . 2431706 .
17. Yaka R, He DY, Phamluong K, Ron D . Pituitary adenylate cyclase-activating polypeptide (PACAP(1-38)) enhances N-methyl-D-aspartate receptor function and brain-derived neurotrophic factor expression via RACK1 . The Journal of Biological Chemistry . 278 . 11 . 9630–8 . March 2003 . 12524444 . 10.1074/jbc.M209141200 . free .
18. Yaka R, Thornton C, Vagts AJ, Phamluong K, Bonci A, Ron D . NMDA receptor function is regulated by the inhibitory scaffolding protein, RACK1 . Proceedings of the National Academy of Sciences of the United States of America . 99 . 8 . 5710–5 . April 2002 . 11943848 . 122836 . 10.1073/pnas.062046299 . 2002PNAS...99.5710Y . free .
19. Croze E, Usacheva A, Asarnow D, Minshall RD, Perez HD, Colamonici O . Receptor for activated C-kinase (RACK-1), a WD motif-containing protein, specifically associates with the human type I IFN receptor . Journal of Immunology . 165 . 9 . 5127–32 . November 2000 . 11046044 . 10.4049/jimmunol.165.9.5127 . free .
20. Edelmann MJ, Iphöfer A, Akutsu M, Altun M, di Gleria K, Kramer HB, Fiebiger E, Dhe-Paganon S, Kessler BM . Structural basis and specificity of human otubain 1-mediated deubiquitination . The Biochemical Journal . 418 . 2 . 379–90 . March 2009 . 18954305 . 10.1042/BJ20081318 .
21. Ozaki T, Watanabe K, Nakagawa T, Miyazaki K, Takahashi M, Nakagawara A . Function of p73, not of p53, is inhibited by the physical interaction with RACK1 and its inhibitory effect is counteracted by pRB . Oncogene . 22 . 21 . 3231–42 . May 2003 . 12761493 . 10.1038/sj.onc.1206382 . free .
22. Yarwood SJ, Steele MR, Scotland G, Houslay MD, Bolger GB . The RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform . The Journal of Biological Chemistry . 274 . 21 . 14909–17 . May 1999 . 10329691 . 10.1074/jbc.274.21.14909 . free .
23. Steele MR, McCahill A, Thompson DS, MacKenzie C, Isaacs NW, Houslay MD, Bolger GB . Identification of a surface on the beta-propeller protein RACK1 that interacts with the cAMP-specific phosphodiesterase PDE4D5 . Cellular Signalling . 13 . 7 . 507–13 . July 2001 . 11516626 . 10.1016/s0898-6568(01)00167-x .
24. Ron D, Jiang Z, Yao L, Vagts A, Diamond I, Gordon A . Coordinated movement of RACK1 with activated betaIIPKC . The Journal of Biological Chemistry . 274 . 38 . 27039–46 . September 1999 . 10480917 . 10.1074/jbc.274.38.27039 . free .
25. Liedtke CM, Yun CH, Kyle N, Wang D . Protein kinase C epsilon-dependent regulation of cystic fibrosis transmembrane regulator involves binding to a receptor for activated C kinase (RACK1) and RACK1 binding to Na+/H+ exchange regulatory factor . The Journal of Biological Chemistry . 277 . 25 . 22925–33 . June 2002 . 11956211 . 10.1074/jbc.M201917200 . free .
26. Hellberg CB, Burden-Gulley SM, Pietz GE, Brady-Kalnay SM . Expression of the receptor protein-tyrosine phosphatase, PTPmu, restores E-cadherin-dependent adhesion in human prostate carcinoma cells . The Journal of Biological Chemistry . 277 . 13 . 11165–73 . March 2002 . 11801604 . 10.1074/jbc.M112157200 . free .
27. Mourton T, Hellberg CB, Burden-Gulley SM, Hinman J, Rhee A, Brady-Kalnay SM . The PTPmu protein-tyrosine phosphatase binds and recruits the scaffolding protein RACK1 to cell-cell contacts . The Journal of Biological Chemistry . 276 . 18 . 14896–901 . May 2001 . 11278757 . 10.1074/jbc.M010823200 . free .
28. Koehler JA, Moran MF . RACK1, a protein kinase C scaffolding protein, interacts with the PH domain of p120GAP . Biochemical and Biophysical Research Communications . 283 . 4 . 888–95 . May 2001 . 11350068 . 10.1006/bbrc.2001.4889 .
29. Battle MA, Maher VM, McCormick JJ . ST7 is a novel low-density lipoprotein receptor-related protein (LRP) with a cytoplasmic tail that interacts with proteins related to signal transduction pathways . Biochemistry . 42 . 24 . 7270–82 . June 2003 . 12809483 . 10.1021/bi034081y .
30. Usacheva A, Smith R, Minshall R, Baida G, Seng S, Croze E, Colamonici O . The WD motif-containing protein receptor for activated protein kinase C (RACK1) is required for recruitment and activation of signal transducer and activator of transcription 1 through the type I interferon receptor . The Journal of Biological Chemistry . 276 . 25 . 22948–53 . June 2001 . 11301323 . 10.1074/jbc.M100087200 . free .
31. Usacheva A, Tian X, Sandoval R, Salvi D, Levy D, Colamonici OR . The WD motif-containing protein RACK-1 functions as a scaffold protein within the type I IFN receptor-signaling complex . Journal of Immunology . 171 . 6 . 2989–94 . September 2003 . 12960323 . 10.4049/jimmunol.171.6.2989 . free .
32. Chang BY, Conroy KB, Machleder EM, Cartwright CA . RACK1, a receptor for activated C kinase and a homolog of the beta subunit of G proteins, inhibits activity of src tyrosine kinases and growth of NIH 3T3 cells . Molecular and Cellular Biology . 18 . 6 . 3245–56 . June 1998 . 9584165 . 108906 . 10.1128/mcb.18.6.3245 .