Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

Abstract

While transfer-RNAs (tRNAs) are known to transport amino acids to ribosome, new functions are being unveiled from tRNAs and their fragments beyond protein synthesis. Here we show that phosphorylation of 90-kDa RPS6K (ribosomal proteins S6 kinase) was enhanced by tRNALeu overexpression under amino acids starvation condition. The phosphorylation of 90-kDa RPS6K was decreased by siRNA specific to tRNALeu and was independent to mTOR (mammalian target of rapamycin) signaling. Among the 90-kDa RPS6K family, RSK1 (ribosomal S6 kinase 1) and MSK2 (mitogen-and stress-activated protein kinase 2) were the major kinases phosphorylated by tRNALeu overexpression. Through SILAC (stable isotope labeling by/with amino acids in cell culture) and combined mass spectrometry analysis, we identified EBP1 (ErbB3-binding protein 1) as the tRNALeu-binding protein. We suspected that the overexpression of free tRNALeu would reinforce ErbB2/ErbB3 signaling pathway by disturbing the interaction between ErbB3 and EBP1, resulting in RSK1/MSK2 phosphorylation, improving cell proliferation and resistance to death. Analysis of samples from patients with breast cancer also indicated an association between tRNALeu overexpression and the ErbB2-positive population. Our results suggested a possible link between tRNALeu overexpression and RSK1/MSK2 activation and ErbB2/ErbB3 signaling.

tRNA Ini CAT inhibits proliferation and promotes apoptosis of laryngeal squamous cell carcinoma cell

“…33 In human epidermal growth factor receptor 2-positive breast cancer cell lines, free tRNA Leu may interact with human epidermal growth factor receptor 3 (ErbB3) and binding protein (EBP1), which in turn activates the ErbB2/ErbB3 signaling pathways, and ultimately promotes cancer cell proliferation. 34 tRNA plays a key role in translation, and its dysregulation may affect cell protein expression. Cancer cells regulate the expression of multiple promoters of cancer progression by regulating the levels of tRNA.…”

Relationship between Ribosomal Protein S6-pS240 Expression and other Prognostic Factors in Non-Special Type Invasive Breast Cancer

“…Increased activity of mTOR, S6K, and RPS6 as well as hyperphosphorylation have been found in different cancer types (neuroblastoma, esophageal, cervical, hematologic, hepatocellular, and breast malignancies, many types of sarcoma, etc.) [12,13,27] .…”

Relationship between tRNA‐derived fragments and human cancers

“…[61][62][63] Moreover, tRNA Leu isoacceptors were found to be highly expressed in human epidermal growth factor receptor-2 (Her2)-positive breast cancer subtypes, which also promoted cancer cell proliferation and survival. 64 However, several studies maintained the lack of relationship between the abundance of tRNA-derived fragments and the number of parent tRNA gene copies. [65][66][67] The expression of tRNA iMet was found to have nothing to do with the abundance of tRNAs.…”