KPNB1-mediated nuclear translocation of PD-L1 promotes non-small cell lung cancer cell proliferation via the Gas6/MerTK signaling pathway

Du, Wenwen; Zhu, Jianjie; Zeng, Yuanyuan; Liu, Ting; Zhang, Yang; Cai, Tingting; Fu, Yulong; Zhang, Weijie; Zhang, Ruochen; Liu, Zeyi; Huang, Jian-An

doi:10.1038/s41418-020-00651-5

Cited by 88 publications

(54 citation statements)

References 54 publications

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“…It is a bioactive form, notably acting as an RNA-binding protein to regulate the mRNA stability [ 38 ]. Nuclear PD-L1 is believed to play an important role in cancer cells independent of its function in immune checkpoint [ 39 , 40 ]. However, for the sake of clarity, we will not discuss further the PD-L1 intracellular species here.…”

Section: The Pd-1/pd-l1 Checkpointmentioning

confidence: 99%

Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

Bailly

Thuru

Quesnel

2021

Cancers

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Upon T-cell receptor stimulation, the Programmed cell Death-1 receptor (PD-1) expressed on T-cells can interact with its ligand PD-L1 expressed at the surface of cancer cells or antigen-presenting cells. Monoclonal antibodies targeting PD-1 or PD-L1 are routinely used for the treatment of cancers, but their clinical efficacy varies largely across the variety of tumor types. A part of the variability is linked to the existence of several forms of PD-L1, either expressed on the plasma membrane (mPD-L1), at the surface of secreted cellular exosomes (exoPD-L1), in cell nuclei (nPD-L1), or as a circulating, soluble protein (sPD-L1). Here, we have reviewed the different origins and roles of sPD-L1 in humans to highlight the biochemical and functional heterogeneity of the soluble protein. sPD-L1 isoforms can be generated essentially by two non-exclusive processes: (i) proteolysis of m/exoPD-L1 by metalloproteases, such as metalloproteinases (MMP) and A disintegrin and metalloproteases (ADAM), which are capable of shedding membrane PD-L1 to release an active soluble form, and (ii) the alternative splicing of PD-L1 pre-mRNA, leading in some cases to the release of sPD-L1 protein isoforms lacking the transmembrane domain. The expression and secretion of sPD-L1 have been observed in a large variety of pathologies, well beyond cancer, notably in different pulmonary diseases, chronic inflammatory and autoimmune disorders, and viral diseases. The expression and role of sPD-L1 during pregnancy are also evoked. The structural heterogeneity of sPD-L1 proteins, and associated functional/cellular plurality, should be kept in mind when considering sPD-L1 as a biomarker or as a drug target. The membrane, exosomal and soluble forms of PD-L1 are all integral parts of the highly dynamic PD-1/PD-L1 signaling pathway, essential for immune-tolerance or immune-escape.

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Section: The Pd-1/pd-l1 Checkpointmentioning

confidence: 99%

Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

Bailly

Thuru

Quesnel

2021

Cancers

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“…Adding further evidence, GAS6/MERTK signalling has been seen to stimulate NSCLC proliferation. Nuclear PD-L1 regulates the synthesis of GAS6 mRNA, promoting GAS6 secretion to activate MERTK signalling pathway [ 12 ]. Interestingly, epiregulin (an EGFR ligand) is predominantly expressed in macrophages in the tumour microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Coregulation of pathways in lung cancer patients with EGFR mutation: therapeutic opportunities

Rosell

Cardona²,

Arrieta

et al. 2021

Br J Cancer

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Epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma are a frequent class of driver mutations. Single EGFR tyrosine kinase inhibitor (TKI) provides substantial clinical benefit, but almost nil radiographic complete responses. Patients invariably progress, although survival can reach several years with post-treatment therapies, including EGFR TKIs, chemotherapy or other procedures. Endeavours have been clinically oriented to manage the acquisition of EGFR TKI-resistant mutations; however, basic principles on cancer evolution have not been considered in clinical trials. For years, evidence has displayed rapidly adaptive mechanisms of resistance to selective monotherapy, posing several dilemmas for the practitioner. Strict adherence to non-small cell lung cancer (NSCLC) guidelines is not always practical for addressing the clinical progression that EGFR-mutant lung adenocarcinoma patients suffer. The purpose of this review is to highlight regulatory mechanisms and signalling pathways that cause therapy-induced resistance to EGFR TKIs. It suggests combinatorial therapies that target EGFR, as well as potential mechanisms underlying EGFR-mutant NSCLC, alerting the reader to clinical opportunities that may lead to a deeper and more durable response. Molecular reprogramming contributes to EGFR TKI resistance, and the compiled information is relevant in understanding the development of new combined targeted strategies in EGFR-mutant NSCLC.

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“…It plays pivotal role in mitotic events during cell cycle ( Zhu et al, 2018 ). It is also involved in various cancers and thus many inhibitors have been developed for KPNB1 to fight against cancer (Du et al, 2020; Yong Hak Kim et al, 2016; Kodama et al, 2017; Sekimoto et al, 2017; T. Wang et al, 2019; Jian Yang et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Decoding nonspecific interactions between human nuclear transport proteins: A computational study

Rathod

2021

Preprint

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The nuclear protein transport between the nucleus and cytosol can be considered a core process of cell regulation. Specially designed proteins in nature such as importins, exportins, and some other transporters facilitate this transport in the cell and control the cellular processes. Prior to cargo transports, the transport proteins first recognize the Nuclear localization signals (NLSs) and Nuclear export signals (NESs) of cargo proteins. NLSs and NESs are short peptides that have specific residues which help to locate them on the groove of transport proteins. However, this transport through the Nuclear pore complexes (NPCs) is not possible without the energy supplying protein, RanGTP (RAs-related nuclear protein guanosine-5-triphosphate). In addition to this, transport proteins bind with other similar protein subunits along with RanGTP to transport cargos. Hence, protein-protein binding is a vital step for the cargo movement. Here, I investigated possible bindings between 12 human nuclear transport proteins using protein-protein docking algorithm. Furthermore, the binding energy of docked complexes have been calculated and compared with the experimentally resolved complexes. Among total 78 possible complexes (12 homodimers and 66 Heterodimers), IPO13-IPO13 and KPNA6-TNPO3 were found to have the highest stability. Another complexes such as IPO4-IPO5, IPO4-IPO9, IPO9-IPO13, IPO9-KPNA6, IPO13-KPNA6, and IPO13-XPO5 have the binding energy greater than the -600 kJ/mol which indicates the stable complex formation.

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KPNB1-mediated nuclear translocation of PD-L1 promotes non-small cell lung cancer cell proliferation via the Gas6/MerTK signaling pathway

Cited by 88 publications

References 54 publications

Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

Coregulation of pathways in lung cancer patients with EGFR mutation: therapeutic opportunities

Decoding nonspecific interactions between human nuclear transport proteins: A computational study

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