The La-Related Proteins, a Family with Connections to Cancer

Abstract

The evolutionarily-conserved La-related protein (LARP) family currently comprises Genuine La, LARP1, LARP1b, LARP4, LARP4b, LARP6 and LARP7. Emerging evidence suggests each LARP has a distinct role in transcription and/or mRNA translation that is attributable to subtle sequence variations within their La modules and specific C-terminal domains. As emerging research uncovers the function of each LARP, it is evident that La, LARP1, LARP6, LARP7 and possibly LARP4a and 4b are dysregulated in cancer. Of these, LARP1 is the first to be demonstrated to drive oncogenesis. Here, we review the role of each LARP and the evidence linking it to malignancy. We discuss a future strategy of targeting members of this protein family as cancer therapy.

Keywords: LARP; LARP1; RBP; RNA-binding; SS-B; cancer; mRNA; proliferation; transcription; translation.

Figure 1

The principal domains common to members of the LARP protein family. Abbreviations: DM15: DM15-repeat containing region (“DM15 region”) also known as “LARP1 motif”; LAM: La Motif; NLS: Nuclear localisation signal; PAM2w: Atypical PAM2 domain; RCD: RNA chaperone domain; RRM: RNA Recognition Motif; RRM-L: RNA recognition-like motif; SUZ-C: SUZ-C domain. (Modified from Bayfield & Maraia, 2010 [20]).

Figure 2

Proposed mechanisms for the interaction between LARP1 and 5'TOPs. (A) Aoki et al. (2013) [45] demonstrated that LARP1 independently binds the terminal adenosine of the poly(A) tail of mRNA and, by simultaneously interacting with 5'cap components, circularises mRNA of 5'TOP-bearing transcripts to enhance their stability; (B) Tcherkezian et al. (2014) [37] showed LARP1 as associating with 5' cap components via its interaction with PABP. LARP1 is complexed with Raptor, which enhances 5'TOP translation, but it is unclear whether this is functionally distinct from its association with PABP/eIF4F; (C) LARP1 in the mTORC1-regulated phosphorylation-dependent switch mechanism described by Fonseca et al. (2015) [38]. Upon mTORC1 inhibition or cell stress (“mTORC1 off”), LARP1 displaces eIF4G and binds both to the 5'TOP sequence and the poly (A) tail of TOP mRNA to create a stable “closed loop” which is translationally inactive. When mTORC1 is active (“mTORC1 on”) 4E-BP1 is phosphorylated whereupon eIF4E is released and returns to the eIF4F complex. At the same time, LARP1 (complexed with Raptor) is activated by mTORC1 and binds PABP. The mRNA then assumes an “open-loop” or translationally active conformation.