RACK1 Function in Cell Motility and Protein Synthesis

Abstract

The receptor for activated C kinase 1 (RACK1) serves as an adaptor for a number of proteins along the MAPK, protein kinase C, and Src signaling pathways. The abundance and near ubiquitous expression of RACK1 reflect its role in coordinating signaling molecules for many critical biological processes, from mRNA translation to cell motility to cell survival and death. Complete deficiency of Rack1 is embryonic lethal, but the recent development of genetic Rack1 hypomorphic mice has highlighted the central role that RACK1 plays in cell movement and protein synthesis. This review focuses on the importance of RACK1 in these processes and places the recent work in the larger context of understanding RACK1 function.

Keywords: RACK1; cancer; cell migration; ribosomes; stress response; translation.

Figure 1.

RACK1 signaling complexes. RACK1 links PKC signaling to the MAP kinase pathway: RACK1 binding to activated PKC leads to the recruitment of JNK into the complex. PKC-mediated phosphorylation of JNK augments JNK activation by the canonical JNK pathway. JNK activates c-Jun, which in turn regulates the transcription of cyclin D1 and RACK1. RACK1 further stabilizes c-Jun by inhibiting its proteasomal degradation through Fbw7. By enhancing JNK–c-Jun activity, RACK1 is implicated in tumorigenesis. RACK1 regulates apoptosis via MAPK and Src: RACK1 binds to MAP3K and activates stress-induced MAPK signaling, which results in apoptosis. In contrast, sequestration of RACK1 into stress granules attenuates MTK1 activation, which results in the inhibition of apoptosis. Binding of RACK1 to Src inhibits Src kinase activity. Upon apoptotic stimuli, inhibition of Src results in the oligomerization of Bax at the outer mitochondrial membrane, caspase activation, and cell death. RACK1 induces the oligomerization of Bax at the outer mitochondrial membrane, caspase activation, and cell death. RACK1 regulates Src activity during migration: Tight regulation of Src activity is necessary to mediate paxillin dynamics at focal adhesions during migration. Src phosphorylates paxillin, and RACK1 regulates paxillin phosphorylation dynamics by binding and releasing Src at its site of action, thereby enabling migration.

Figure 2.

Schematic representation of RACK1’s putative role in translation initiation. (A) RACK1 and the antiassociation factor eIF6 bind 40S and 60S, respectively (1). RACK1 recruits PKCβII to the ribosome, and PKCβII phosphorylates eIF6 on serine 235 (2). Release of phosphorylated eIF6 allows 80S formation on the mRNA (3). (B) The ternary complex (eIF2-GTP-tRNAi^Met) (1) is recruited to 40S with a multimeric complex composed of eIF1A, eIF1, eIF5, and eIF3. eIF3 binding to RACK1 stabilizes the ternary complex on the ribosome (2). The 43S complex is then recruited to the mRNA and stabilized through an eIF3-eIF4G interaction (3). The 48S complex scans the mRNA to reach the initiation codon (AUG).

Figure 3.

Schematic representation of RACK1 in miRNA-mediated repression. RACK1 binds translating ribosomes, where it recruits the Ago2–let-7 complex to silence the mRNA translation of let-7 targets.