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Amino acid transporters (AATs) facilitate nutrient uptake and nutrient exchange between cancer and stromal cells. The posttranslational modification (PTM) of transporters is an important mechanism that tumor-associated cells use to dynamically regulate their function and stability in response to microenvironmental cues. In this review, we summarize recent findings that demonstrate the significance of N-glycosylation, phosphorylation, and ubiquitylation for the function of AATs. We also highlight powerful approaches that hijack the PTM machinery that could be used as therapeutics or tools to modulate transporter activity.

Section snippetsIntroduction: tumor microenvironment and cancer metabolism

The tumor microenvironment (TME) consists of cells, extracellular matrix, nutrients, and ions, and directly regulates the metabolism and activity of tumor-resident cell types. Rewired metabolism is a hallmark of cancer cells that occurs in response to genetic drivers of malignancy and environmental stressors, contributing to the ability of cancer cells to proliferate, survive, and migrate within their local TME [1]. There are specific nutrients in the TME, such as amino acids, that

Solute carriers are regulated by posttranslational modifications

Posttranslational modifications (PTMs), including phosphorylation, glycosylation, and ubiquitylation, are integral for the structure and function of SLCs within their lipid environment and regulate their trafficking, maturation, and turnover.

Approximately two-thirds of annotated SLCs are at least partially localized to the plasma membrane, where they would be expected to interface with nutrients in the TME [15]. Many SLCs are localized to other organelles and may be more important for

Posttranslational modifications affect transporter stability

Identifying modified residues for an AAT of interest is often the first hurdle to studying how PTMs may influence their function. Several tools and databases are readily accessible to predict posttranslationally modified sites, as reviewed in Ref. [26]. Site-directed mutagenesis is frequently used to replace the putatively modified residue with a nonmodifiable amino acid (e.g. serine to alanine, asparagine to glutamine) and validate the functional role of the modification. The alanine, serine,

Chemical inducers of proximity (targeted protein degradation)

There are recent and exciting advancements in developing chemical inducers of proximity (CIPs) that promote protein–protein interactions and induce (or remove) PTMs, as reviewed in Ref. [46]. The ‘dTAG system’ is a model, genetically encoded CIP that facilitates the interaction between target protein fused to a mutant FKBP12F36N domain and the Cereblon E3 ligase to promote the target protein’s ubiquitylation and subsequent proteasomal degradation [47]. Bensimon et al. recently showed that the

Conclusion

Recent discoveries have shown how important PTMs are for regulating the stability, membrane expression, and subcellular distribution of AATs. Directly manipulating these modifications genetically or pharmacologically is a promising strategy to (de)stabilize AATs and affect their activity in cancer cells or other tumor-associated cell types. These tools also show strong potential to help us better understand how AAT activity is regulated by nutrients and other factors present in the complex and

Editorial disclosure statement

Given the role as Guest Editor, Seth Parker had no involvement in the peer review of the article and has no access to information regarding its peer-review. Full responsibility for the editorial process of this article was delegated to Thekla Cordes.

Declaration of Competing Interest

The authors declare that they have no conflicts of interest.

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