Our understanding of the enigmatic receptor for activated C-kinase 1 (RACK1) protein has increased dramatically in recent years from its original identification as an anchoring protein for protein kinase C (PKC)(Ron et al., 1994a). By virtue of its ability to coordinate the interaction of key signaling molecules, RACK1 is becoming widely perceived as playing a central role in critical biological responses, such as cell growth. RACK1 is a 36-kDa protein (SwissProt accession no. P25388) containing seven internal Trp-Asp 40 (WD40) repeats (Fig 1A), with a consensus X6–94-[GH-X23–41-WD] N4–8 (where N number of WD repeats). It is homologous to the G protein subunit, having 42% identity with many conserved amino acid substitutions. The WD repeats of RACK1 can be predicted to form a seven-bladed propeller structure (Sondek and Siderovski, 2001; Steele et al., 2001), with each blade made up of-sheets as shown in crystallographic studies for G (Wall et al., 1995; Sondek et al., 1996). The WD repeat sequence of RACK1 is highly conserved in a diverse range of species, including plants (Kwak et al., 1997) and genetically malleable species such as Drosophila melanogaster and Caenorhabditis elegans (Bini et al., 1997). Positioning of RACK1 WD repeats is even maintained in the alga Chlamydomonas reinhardtii (Schloss, 1990), which diverged from the forerunners of the plant and animal kingdoms some 600 million to 1 billion years ago. This has prompted the suggestion that the biological function of RACK1 was established before this separation occurred (Neer et al., 1994). Indeed, RACK1 is ubiquitously expressed in the tissues of higher mammals and humans (Guillemot et al., 1989), including brain, liver, and spleen, suggesting that it has an important functional role in most, if not all, cells (Chou et al., 1999).

RACK1 was originally cloned from both a chicken liver cDNA library and a human B-lymphoblastoid cell line (Guillemot et al., 1989) and referred to as C12. 3 or H12. 3, respectively. The name RACK1 was adopted by the Mochly-Rosen group to describe its ability to bind activated PKC. This was because the rat gene product passed experimental criteria similar to those used to identify protein A-kinase anchoring proteins (Edwards and Scott, 2000). These criteria were originally established by Ron et al.(1994) and recently refined by Dorn and Mochly Rosen (2002): 1) injection of cells with purified RACK should block PKC-mediated cell processes. Similarly, 2) delivery of peptides into cells should block the interaction between a particular PKC isozyme and its RACK, and this should specifically impair a known cellular function of that isozyme. 3) Injection of peptides that induce an interaction between a particular PKC isozyme and its RACK should selectively activate that isozyme, and 4) RACK should bind PKC in the presence of PKC activators (Ron and Mochly-Rosen, 1994; Dorn and Mochly-Rosen, 2002). The first report on the structure and genomic organization of a mammalian RACK was carried out on the porcine RACK1 gene (Chou et al., 1999), which has almost 100% identity at the protein level with its vertebrate homologs. The RACK1 gene promoter contains a number of transcription factor binding sites including serum response element, AP1, SP1, NF1, and YY1 (Chou et al., 1999). Binding of serum response factor to the serum response element is known to be essential for the transcription of certain genes in response to growth factors; accordingly, RACK1 expression was found to be up-regulated after serum stimulation (Chou et al., 1999). That the activity of the RACK1 gene is controlled by growth-