PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt

Uche, Uzodinma; Piccirillo, Ann; Kataoka, Shunsuke; Grebinoski, Stephanie; D’Cruz, Louise M.; Kane, Larry

doi:10.1084/jem.20172018

Cited by 37 publications

(37 citation statements)

References 45 publications

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“…PIP 3 interacts with the pleckstrin homology domain of protein kinase B (AKT), causing a conformational change that allows PDK1 (kinase 3-phosphoinositide–dependent protein kinase-1) to partially activate AKT by phosphorylating threonine 308 (T308). Full activation of AKT is achieved by mTORC2-mediated phosphorylation at serine 473 (S473) and facilitates such processes as cell growth, cell cycle progression, and cell survival [4].…”

Section: Introductionmentioning

confidence: 99%

mTOR Links Tumor Immunity and Bone Metabolism: What are the Clinical Implications?

Irelli

Sirufo

Scipioni

et al. 2019

IJMS

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Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) plays a crucial role in the control of cellular growth, proliferation, survival, metabolism, angiogenesis, transcription, and translation. In most human cancers, alterations to this pathway are common and cause activation of other downstream signaling pathways linked with oncogenesis. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both tumor immunity and angiogenesis. Inflammation is a hallmark of cancer, playing a central role in the tumor dynamics, and immune cells can exert antitumor functions or promote the growth of cancer cells. In this context, mTOR may regulate the activity of macrophages and T cells by regulating the expression of cytokines/chemokines, such as interleukin (IL)-10 and transforming growth factor (TGF-β), and/or membrane receptors, such as cytotoxic T-Lymphocyte protein 4 (CTLA-4) and Programmed Death 1 (PD-1). Furthermore, inhibitors of mammalian target of rapamycin are demonstrated to actively modulate osteoclastogenesis, exert antiapoptotic and pro-differentiative activities in osteoclasts, and reduce the number of lytic bone metastases, increasing bone mass in tumor-bearing mice. With regard to the many actions in which mTOR is involved, the aim of this review is to describe its role in the immune system and bone metabolism in an attempt to identify the best strategy for therapeutic opportunities in the metastatic phase of solid tumors.

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Section: Introductionmentioning

confidence: 99%

mTOR Links Tumor Immunity and Bone Metabolism: What are the Clinical Implications?

Irelli

Sirufo

Scipioni

et al. 2019

IJMS

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“…In line with this, PIK3IPI implicated in inhibition of T cell activation was upregulated in the CAR neg/low population ( Figure 4 A), further confirming the low activation status of these cells. 25 Although only slightly upregulated, both interferon-induced transmembrane proteins covered by the panel, IFITM2 and IFITM3 , were significantly higher in CAR neg/low cells than in untransduced or CAR high cells ( Figure 4 F).…”

Section: Resultsmentioning

confidence: 95%

“…Thus, these changes were most likely due to the exposure to LV vectors. This referred to the negative regulators of proliferation and inhibitors of T cell activation CD37 and PIK3IPI , respectively ( Figure 4 A), 25 , 26 as well as co-stimulatory and phenotype markers such as CD27 , CD7 , CD62L (SELL) , and TCF7 ( Figures 4 A and 4G). Typical markers for apoptosis induction ( CASP5 ) ( Figure 4 D) and exhaustion ( LIF , C10orf54 ) ( Figure 4 E) were also induced upon exposure to LV particles.…”

Section: Resultsmentioning

confidence: 99%

Monitoring CAR T cell generation with a CD8-targeted lentiviral vector by single-cell transcriptomics

Charitidis

Adabi

Thalheimer

et al. 2021

Molecular Therapy - Methods & Clinical Development

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Quantifying gene expression in individual cells can substantially improve our understanding about complex genetically engineered cell products such as chimeric antigen receptor (CAR) T cells. Here we designed a single-cell RNA sequencing (scRNA-seq) approach to monitor the delivery of a CD19-CAR gene via lentiviral vectors (LVs), i.e., the conventional vesicular stomatitis virus (VSV)-LV and the CD8-targeted CD8-LV. LV-exposed human donor peripheral blood mononuclear cells (PBMCs) were evaluated for a panel of 400 immune response-related genes including LV-specific probes. The resulting data revealed a trimodal expression for the CAR and CD8A , demanding a careful distribution-based identification of CAR T cells and CD8+ lymphocytes in scRNA-seq analysis. The fraction of T cells expressing high CAR levels was in concordance with flow cytometry results. More than 97% of the cells hit by CD8-LV expressed the CD8A gene. Remarkably, the majority of the potential off-target cells were in fact on-target cells, resulting in a target cell selectivity of more than 99%. Beyond that, differential gene expression analysis revealed the upregulation of restriction factors in CAR -negative cells, thus explaining their protection from CAR gene transfer. In summary, we provide a workflow and subsetting approach for scRNA-seq enabling reliable distinction between transduced and untransduced cells during CAR T cell generation.

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“…T cell receptor (TCR) has been shown to regulate ADAM10- and ADAM17-induced shedding of the immune check point molecules Lag3, Tim-3 [ 85 ] and PIK3IP1 (transmembrane inhibitor of PI3K or TrIP) [ 86 ], a putative transmembrane regulator of PI3K, with distinct mechanisms. To our knowledge, a “sheddase recognition motif” has not yet been identified in protein target sequences.…”

Section: Adams Substrates and Partnersmentioning

confidence: 99%

ADAM10 Site-Dependent Biology: Keeping Control of a Pervasive Protease

Tosetti

Alessio

Poggi

et al. 2021

IJMS

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Enzymes, once considered static molecular machines acting in defined spatial patterns and sites of action, move to different intra- and extracellular locations, changing their function. This topological regulation revealed a close cross-talk between proteases and signaling events involving post-translational modifications, membrane tyrosine kinase receptors and G-protein coupled receptors, motor proteins shuttling cargos in intracellular vesicles, and small-molecule messengers. Here, we highlight recent advances in our knowledge of regulation and function of A Disintegrin And Metalloproteinase (ADAM) endopeptidases at specific subcellular sites, or in multimolecular complexes, with a special focus on ADAM10, and tumor necrosis factor- convertase (TACE/ADAM17), since these two enzymes belong to the same family, share selected substrates and bioactivity. We will discuss some examples of ADAM10 activity modulated by changing partners and subcellular compartmentalization, with the underlying hypothesis that restraining protease activity by spatial segregation is a complex and powerful regulatory tool.

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PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt

Cited by 37 publications

References 45 publications

mTOR Links Tumor Immunity and Bone Metabolism: What are the Clinical Implications?

mTOR Links Tumor Immunity and Bone Metabolism: What are the Clinical Implications?

Monitoring CAR T cell generation with a CD8-targeted lentiviral vector by single-cell transcriptomics

ADAM10 Site-Dependent Biology: Keeping Control of a Pervasive Protease

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