LARP4

Official Full Name

La ribonucleoprotein 4

Organism

Homo sapiens

GeneID

113251

Background

Enables mRNA 3'-UTR binding activity and poly(A) binding activity. Involved in cytoskeleton organization; positive regulation of translation; and regulation of cell morphogenesis. Located in cytoplasmic stress granule and cytosolic small ribosomal subunit. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

PP13296;

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Detailed Information

Recent Progress

It is universally acknowledged that messenger RNA function is controlled by the 3' poly(A) tail (PAT) and poly(A)-binding protein (PABP). And the La-related protein-4 (LARP4) protein, which is coded by the larp4 gene, binds poly(A) and PABP.

Non-coding RNAs (ncRNAs) have been shown to regulate gene expression involved in tumor progression of multiple malignancies. Previous studies indicated that large tumor suppressor kinase 1 (LATS1), a core part of Hippo signaling pathway, functions as a tumor suppressor in gastric cancer (GC). A novel circular RNA_LARP4 (circLARP4) was identified to sponge miR-424. According to the results, increased miR-424 expression or decreased LATS1 expression was associated with pathological stage and unfavorable prognosis of GC patients. Furthermore, circLARP4 was mainly localized in the cytoplasm and inhibited biological behaviors of GC cells by sponging miR-424. The expression of circLARP4 was downregulated in GC tissues and represented an independent prognostic factor for overall survival of GC patients. This indicated that circLARP4 may act as a novel tumor suppressive factor and a potential biomarker in GC (Fig.1).

Fig. 1. The effects of circLARP4 on GC cell proliferation and invasion. (Zhang et al, 2017)

It was previously identified that LARP4 as one of several genes that regulate the shape of PC3 prostate cancer cells. In one study, researchers showed that LARP4 depletion induces cell elongation in PC3 cells and MDA-MB-231 breast cancer cells. LARP4 depletion increases cell migration and invasion, as well as inducing invasive cell protrusions. Conversely, LARP4 over-expression reduces cell elongation and increases cell circularity. LARP4 mutations are found in a variety of cancers. Introduction of some of these cancer-associated mutations, including a truncation mutant, into LARP4 enhances its effects on cell morphology. The truncation mutant showed enhanced interaction with PABP. Thus it was proposed that LARP4 inhibits migration and invasion of cancer cells, and that some cancer-associated mutations stimulate these effects of LARP4.

LARP4 mRNA contains a translation-dependent, coding region determinant (CRD) of instability that limits its expression. Separately, overexpression of the most limiting tRNA increases LARP4 levels and reveals its functional activity, net lengthening of the PATs of heterologous mRNAs, including ribosomal protein (RP) mRNAs. Genetic deletion of cellular LARP4 decreases PAT length and RPmRNA stability. This activity of LARP4 requires its PABP-interaction domain and the RNA-binding module which was shown to be sensitive to poly(A) 3'-termini, consistent with protection from deadenylation. The results indicated that LARP4 is a posttranscriptional regulator of ribosomal protein production in mammalian cells and suggested that this activity can be controlled by tRNA levels.

Another group of researchers found a conserved AU-rich element (ARE) in human LARP4 mRNA 3’-UTR. This ARE significantly decreased the stability of β-globin reporter mRNA. It was found that over-expression of Tristetraprolin (TTP) decreased cellular LARP4 levels. RNA co-immunoprecipitation showed that TTP specifically associated with LARP4 mRNA in vivo. Consistent with this finding, mouse LARP4 accumulated to higher levels in TTP gene knock out (KO) cells than in control cells. Stimulation with TNFα rapidly induced TTP but robustly decreased LARP4 with coincident time course. The TNFα-induced TTP pulse was followed by a transient decrease in LARP4 mRNA that was quickly followed by a subsequent transient decrease in LARP4 protein. Involvement of LARP4 as a target of TNFα-TTP regulation provides a clue as to how its functional activity may be used in a physiologic pathway.

References:

Zhang, J., Liu, H., Hou, L., Wang, G., Zhang, R., & Huang, Y., et al. (2017). Circular rna_larp4 inhibits cell proliferation and invasion of gastric cancer by sponging mir-424-5p and regulating lats1 expression. Molecular Cancer, 16(1), 151.
Seetharaman, S., Flemyng, E., Shen, J., Conte, M. R., & Ridley, A. J. (2016). The rna‐binding protein larp4 regulates cancer cell migration and invasion. Cytoskeleton, 73(11), 680-690.
Mattijssen, S., Arimbasseri, A. G., Iben, J. R., Gaidamakov, S., Lee, J., & Hafner, M., et al. (2017). Larp4 mrna codon-trna match contributes to larp4 activity for ribosomal protein mrna poly(a) tail length protection. eLife,6,(2017-09-05), 6, e28889.
Mattijssen, S., & Maraia, R. J. (2015). Larp4 is regulated by tnfα in a tristetraprolin (ttp)-dependent manner. Molecular & Cellular Biology, 36(4).
Mattijssen, S., & Maraia, R. J. (2015). Larp4 is regulated by tumor necrosis factor alpha in a tristetraprolin-dependent manner. Molecular & Cellular Biology, 36(4), 574-584.

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