LARP1 explained

La-related protein 1 (LARP1) is a 150 kDa protein that in humans is encoded by the LARP1 gene.^{[1] [2] [3]} LARP1 is a novel target of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, a circuitry often hyperactivated in cancer which regulates cell growth and proliferation primarily through the regulation of protein synthesis.^[4]

Function

LARP1 is the largest of a 7-member family of LARP proteins (others are: LARP1B, LARP3 (aka genuine La or SSB), LARP4A, LARP4B, LARP6 and LARP7).^[5] All LARP proteins, including human LARPs, contain 2 conserved regions. The first conserved region shares homology with La proteins (called the La motif, see SSB) whereas the second conserved region (called the LA- motif) is restricted to LARP proteins. LARP1 and 1B also contain a conserved "DM15 region" within their C-terminus.^[6] This region is unique and has been shown to be required for RNA-binding. Mouse Larp1 is expressed in dorsal root ganglia and spinal cord, as well as in developing organs characterized by epithelial-mesenchymal interactions. Human LARP1 is present at low levels in normal, non-embryonic cells but is highly expressed in epithelial cancers (such as ovarian, colorectal, prostate, non-small cell lung, hepatocellular and cervical cancers).^{[7] [8] [9] [10]} Some studies have shown that high levels of LARP1 protein correlate with worse prognosis in cancer patients.^{[11] [12]}

LARP1 binds to and regulates the translation of terminal oligopyrimidine motif (TOP mRNAs) and can directly interact with the 5' cap of mRNAs.^{[13] [14]} It has also been shown to interact with the 3' end and coding regions (CDS) of other genes. LARP1 protein colocalizes with stress granules and P-bodies,^[15] which function in RNA storage and degradation. It has been suggested that LARP1 functions in P-bodies to attenuate the abundance of conserved Ras-MAPK mRNAs. The cluster of LARP1 homologs may function to control the expression of key developmental regulators.

Several studies have demonstrated that LARP1 deficiency selectively affects the recruitment of TOP mRNAs to polysomes. In some cancer cells, LARP1 deficiency reduces proliferation and activates apoptotic cell death. Even though a decrease abundance of proteins encoded by TOP mRNAs has been reported in LARP1 silenced cells, some researchers believe that this can be explained simply by the reduced number of TOP mRNA transcripts in LARP1-deficient cells.

Further reading

• Horke S, Reumann K, Schweizer M, Will H, Heise T . Nuclear trafficking of La protein depends on a newly identified nucleolar localization signal and the ability to bind RNA . The Journal of Biological Chemistry . 279 . 25 . 26563–70 . June 2004 . 15060081 . 10.1074/jbc.M401017200 . free .
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP . Large-scale characterization of HeLa cell nuclear phosphoproteins . Proceedings of the National Academy of Sciences of the United States of America . 101 . 33 . 12130–5 . August 2004 . 15302935 . 514446 . 10.1073/pnas.0404720101 . 2004PNAS..10112130B . free .
• Jin J, Smith FD, Stark C, Wells CD, Fawcett JP, Kulkarni S, Metalnikov P, O'Donnell P, Taylor P, Taylor L, Zougman A, Woodgett JR, Langeberg LK, Scott JD, Pawson T . Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization . Current Biology . 14 . 16 . 1436–50 . August 2004 . 15324660 . 10.1016/j.cub.2004.07.051 . 2371325 . free . 2004CBio...14.1436J .
• Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP . A probability-based approach for high-throughput protein phosphorylation analysis and site localization . Nature Biotechnology . 24 . 10 . 1285–92 . October 2006 . 16964243 . 10.1038/nbt1240 . 14294292 .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–48 . November 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .

Notes and References

1. Nagase T, Ishikawa K, Suyama M, Kikuno R, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 5 . 5 . 277–86 . October 1998 . 9872452 . 10.1093/dnares/5.5.277 . free .
2. Chauvet S, Maurel-Zaffran C, Miassod R, Jullien N, Pradel J, Aragnol D . dlarp, a new candidate Hox target in Drosophila whose orthologue in mouse is expressed at sites of epithelium/mesenchymal interactions . Developmental Dynamics . 218 . 3 . 401–13 . July 2000 . 10878606 . 10.1002/1097-0177(200007)218:3<401::AID-DVDY1009>3.0.CO;2-6 . free .
3. Web site: Entrez Gene: LARP1 La ribonucleoprotein domain family, member 1.
4. Tcherkezian J, Cargnello M, Romeo Y, Huttlin EL, Lavoie G, Gygi SP, Roux PP . Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5'TOP mRNA translation. . Genes Dev . 28 . 4 . 357–71 . Feb 2014 . 24532714 . 3937514 . 10.1101/gad.231407.113 .
5. Bousquet-Antonelli C, Deragon JM . A comprehensive analysis of the La-motif protein superfamily . RNA . 15 . 5 . 750–64 . May 2009 . 19299548 . 2673062 . 10.1261/rna.1478709 .
6. Lahr RM, Mack SM, Héroux A, Blagden SP, Bousquet-Antonelli C, Deragon JM, Berman AJ . The La-related protein 1-specific domain repurposes HEAT-like repeats to directly bind a 5'TOP sequence . Nucleic Acids Research . 43 . 16 . 8077–88 . September 2015 . 26206669 . 4652764 . 10.1093/nar/gkv748 .
7. Stavraka C, Blagden S . The La-Related Proteins, a Family with Connections to Cancer . Biomolecules . 5 . 4 . 2701–22 . October 2015 . 26501340 . 4693254 . 10.3390/biom5042701 . free .
8. Mura M, Hopkins TG, Michael T, Abd-Latip N, Weir J, Aboagye E, Mauri F, Jameson C, Sturge J, Gabra H, Bushell M, Willis AE, Curry E, Blagden SP . LARP1 post-transcriptionally regulates mTOR and contributes to cancer progression . Oncogene . 34 . 39 . 5025–36 . September 2015 . 25531318 . 4430325 . 10.1038/onc.2014.428 .
9. Hopkins TG, Mura M, Al-Ashtal HA, Lahr RM, Abd-Latip N, Sweeney K, Lu H, Weir J, El-Bahrawy M, Steel JH, Ghaem-Maghami S, Aboagye EO, Berman AJ, Blagden SP . The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer . Nucleic Acids Research . 44 . 3 . 1227–46 . February 2016 . 26717985 . 4756840 . 10.1093/nar/gkv1515 .
10. Xie C, Huang L, Xie S, Xie D, Zhang G, Wang P, Peng L, Gao Z . LARP1 predict the prognosis for early-stage and AFP-normal hepatocellular carcinoma . Journal of Translational Medicine . 11 . 272 . October 2013 . 24159927 . 3814951 . 10.1186/1479-5876-11-272 . free .
11. Ye L, Lin ST, Mi YS, Liu Y, Ma Y, Sun HM, Peng ZH, Fan JW . Overexpression of LARP1 predicts poor prognosis of colorectal cancer and is expected to be a potential therapeutic target . Tumour Biology . 37 . 11 . 14585–14594 . November 2016 . 27614686 . 5126195 . 10.1007/s13277-016-5332-3 .
12. Xu Z, Xu J, Lu H, Lin B, Cai S, Guo J, Zang F, Chen R . LARP1 is regulated by the XIST/miR-374a axis and functions as an oncogene in non-small cell lung carcinoma . Oncology Reports . 38 . 6 . 3659–3667 . December 2017 . 29039571 . 10.3892/or.2017.6040 . free .
13. Hong S, Freeberg MA, Han T, Kamath A, Yao Y, Fukuda T, Suzuki T, Kim JK, Inoki K . LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs . eLife . 6 . June 2017 . 28650797 . 5484620 . 10.7554/elife.25237 . free .
14. Lahr RM, Fonseca BD, Ciotti GE, Al-Ashtal HA, Jia JJ, Niklaus MR, Blagden SP, Alain T, Berman AJ . La-related protein 1 (LARP1) binds the mRNA cap, blocking eIF4F assembly on TOP mRNAs . eLife . 6 . April 2017 . 28379136 . 5419741 . 10.7554/elife.24146 . free .
15. Nykamp K, Lee MH, Kimble J . C. elegans La-related protein, LARP-1, localizes to germline P bodies and attenuates Ras-MAPK signaling during oogenesis . RNA . 14 . 7 . 1378–89 . July 2008 . 18515547 . 2441978 . 10.1261/rna.1066008 .