| La-related protein 1 (LARP1) is an RNA-binding protein of the La superfamily that integrates post-transcriptional control of gene expression with mTORC1-dependent signaling, acting as a key regulator of mRNAs bearing 5′ terminal oligopyrimidine (5′TOP) motifs that encode ribosomal proteins and translation factors. The protein contains conserved La and RNA-recognition elements together with a C‑terminal DM15 region that forms a structured interface for binding both the 5′ cap and adjacent oligopyrimidine tract of TOP mRNAs, creating a selective docking platform at their 5′ ends. Through this cap–TOP interaction, LARP1 directly engages the mRNA 5′ terminus and can block assembly of the eIF4F initiation complex, which positions it as a critical determinant of whether TOP mRNAs enter active translation or remain repressed under distinct signaling conditions. Association with mTORC1 links LARP1 activity to nutrient and growth factor signals, and phosphorylation by mTORC1 at specific serine and threonine residues modulates its affinity for TOP mRNA 5′ ends and alters its capacity to compete with canonical cap-binding factors such as eIF4E. Under conditions of high mTORC1 activity, phosphorylated LARP1 exhibits reduced inhibitory binding at the cap, allowing increased recruitment of eIF4F and promoting translation of TOP mRNAs that support ribosome biogenesis and protein synthesis, while, under mTORC1 inhibition, LARP1 preferentially binds and shields the 5′TOP region, maintaining translational repression. LARP1 also interacts with poly(A)-binding protein and associates with a broad mRNA interactome enriched for transcripts in cancer-related pathways, including mTOR itself, whose mRNA stability is enhanced by LARP1 binding, coupling control of translation initiation with regulation of mRNA turnover for selected signaling components. This dual role in cap-dependent translational gating and mRNA stabilization situates LARP1 at a nodal point where mTORC1 signaling can fine-tune both the synthesis and persistence of proteins involved in cell growth, migration, and invasion. Dysregulated LARP1 expression has been observed in epithelial malignancies such as cervical and non-small cell lung cancer, where elevated LARP1 correlates with more advanced disease and poorer prognosis and functionally associates with increased migration, invasion, anchorage-independent growth, and in vivo tumorigenesis, consistent with its role in supporting mTOR pathway output and cancer-associated mRNA programs. |
