Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation

Patsoukis, Nikolaos; Duke‐Cohan, Jonathan S.; Chaudhri, Apoorvi; Aksoylar, Halil‐Ibrahim; Wang, Qi; Council, Asia; Berg, Anders H.; Freeman, Gordon J.; Boussiotis, Vassiliki A.

doi:10.1038/s42003-020-0845-0

Cited by 103 publications

(113 citation statements)

References 69 publications

(104 reference statements)

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“…By combining biochemical and biophysical methods as well as confocal microscopy, this study revealed that this alternative mode of PD-1:SHP-2 interaction preferentially occurred in live cells, where, after PD-1 phosphorylation, SHP-2, via its N-SH2 and C-SH2 domains, could bridge two phosphorylated pY-ITSM residues on two PD-1 molecules localized at the plasma membrane, forming a PD-1:PD-1 dimer ( Fig. 3B ) ( 70 ). SHP-2 interaction with two tandemly connected ITSM phosphopeptides induced robust SHP-2 enzymatic activation, suggesting that a combination of strong binding ITSM motifs can form an SHP-2–dependent PD-1 dimer and simultaneously activate the phosphatase.…”

Section: Mechanisms and Targets Of Pd-1 Signalingmentioning

confidence: 80%

“…Almost in parallel, it was determined that besides binding of the two SHP-2 SH2 domains in tandem with the two phosphotyrosines of the PD-1 cytoplasmic tail, SHP-2 and PD-1 have the biophysical properties to interact via engagement of both SHP-2 SH2 domains with phosphorylated PD-1–ITSM Y248 from two different PD-1 molecules ( 70 ). By combining biochemical and biophysical methods as well as confocal microscopy, this study revealed that this alternative mode of PD-1:SHP-2 interaction preferentially occurred in live cells, where, after PD-1 phosphorylation, SHP-2, via its N-SH2 and C-SH2 domains, could bridge two phosphorylated pY-ITSM residues on two PD-1 molecules localized at the plasma membrane, forming a PD-1:PD-1 dimer ( Fig.…”

Section: Mechanisms and Targets Of Pd-1 Signalingmentioning

confidence: 99%

“…SHP-2 interaction with two tandemly connected ITSM phosphopeptides induced robust SHP-2 enzymatic activation, suggesting that a combination of strong binding ITSM motifs can form an SHP-2–dependent PD-1 dimer and simultaneously activate the phosphatase. The discovery of this alternative binding mode that leads to the formation of an SHP-2–dependent PD-1 dimer explains how PD-1/SHP-2 interaction can occur by the involvement of only one PD-1 phosphotyrosine ( 61 – 63 ) and resolves a long-standing conundrum of how a single docking site within the PD-1 cytoplasmic tail can activate SHP-2 and mediate PD-1 inhibitory function ( 70 ). Development of novel techniques to monitor the activity of SHP-2 in live cells will shed light on the detailed interplay between these PD-1:SHP-2 interaction modes in live cells.…”

Section: Mechanisms and Targets Of Pd-1 Signalingmentioning

confidence: 99%

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Revisiting the PD-1 pathway

et al. 2020

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Programmed Death-1 (PD-1; CD279) is an inhibitory receptor induced in activated T cells. PD-1 engagement by its ligands, PD-L1 and PD-L2, maintains peripheral tolerance but also compromises anti-tumor immunity. Blocking antibodies against PD-1 or its ligands have revolutionized cancer immunotherapy. However, only a fraction of patients develop durable antitumor responses. Clinical outcomes have reached a plateau without substantial advances by combinatorial approaches. Thus, great interest has recently emerged to investigate, in depth, the mechanisms by which the PD-1 pathway transmits inhibitory signals with the goal to identify molecular targets for improvement of the therapeutic success. These efforts have revealed unpredictable dimensions of the pathway and uncovered novel mechanisms involved in PD-1 and PD-L1 regulation and function. Here, we provide an overview of the recent advances on the mechanistic aspects of the PD-1 pathway and discuss the implications of these new discoveries and the gaps that remain to be filled.

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Section: Mechanisms and Targets Of Pd-1 Signalingmentioning

confidence: 80%

Section: Mechanisms and Targets Of Pd-1 Signalingmentioning

confidence: 99%

Section: Mechanisms and Targets Of Pd-1 Signalingmentioning

confidence: 99%

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Revisiting the PD-1 pathway

et al. 2020

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“…Though both the motifs act as docking sites for the recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, mutational studies have revealed that ITSM phosphotyrosine, which preferentially recruits SHP-2, is crucial for the key inhibitory function of PD-1 resulting in down-modulation of intracellular signaling. However, the exact molecular mechanisms of PD-1-mediated inhibition of T lymphocytes are still being scrutinized and are therefore under investigation [49,50]. The signal becomes functional mainly when the PD-1 molecules colocalize with CD3/CD28 receptors, where simultaneous TCR (T Cell Receptor) signaling is considered pivotal for SHP-2 to dephosphorylate the TCR activation molecules ZAP70 and CD3δ, leading to the repression of the downstream PI3K/Akt pathway associated with TCR signals to manifest negative T cell regulation by PD-1 [51].…”

Section: Species Reported Population Studiedmentioning

confidence: 99%

Delicate Role of PD-L1/PD-1 Axis in Blood Vessel Inflammatory Diseases: Current Insight and Future Significance

Veluswamy

Wacker

Scherner

et al. 2020

IJMS

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Immune checkpoint molecules are the antigen-independent generator of secondary signals that aid in maintaining the homeostasis of the immune system. The programmed death ligand-1 (PD-L1)/PD-1 axis is one among the most extensively studied immune-inhibitory checkpoint molecules, which delivers a negative signal for T cell activation by binding to the PD-1 receptor. The general attributes of PD-L1’s immune-suppressive qualities and novel mechanisms on the barrier functions of vascular endothelium to regulate blood vessel-related inflammatory diseases are concisely reviewed. Though targeting the PD-1/PD-L1 axis has received immense recognition—the Nobel Prize in clinical oncology was awarded in the year 2018 for this discovery—the use of therapeutic modulating strategies for the PD-L1/PD-1 pathway in chronic inflammatory blood vessel diseases is still limited to experimental models. However, studies using clinical specimens that support the role of PD-1 and PD-L1 in patients with underlying atherosclerosis are also detailed. Of note, delicate balances in the expression levels of PD-L1 that are needed to preserve T cell immunity and to curtail acute as well as chronic infections in underlying blood vessel diseases are discussed. A significant link exists between altered lipid and glucose metabolism in different cells and the expression of PD-1/PD-L1 molecules, and its possible implications on vascular inflammation are justified. This review summarizes the most recent insights concerning the role of the PD-L1/PD-1 axis in vascular inflammation and, in addition, provides an overview exploring the novel therapeutic approaches and challenges of manipulating these immune checkpoint proteins, PD-1 and PD-L1, for suppressing blood vessel inflammation.

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“…1A). A dominant hypothesis for the control of SHP-1 and SHP-2 activity is allosteric activation, whereby these enzymes are inactive in the cytoplasm but increase their catalytic activity when their SH2 domains are engaged at the membrane (9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Determination of the molecular reach of the protein tyrosine phosphatase SHP-1

Clemens

Kutuzov

Bayer

et al. 2020

Preprint

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Immune receptor signalling proceeds by the binding of enzymes to their cytoplasmic tails before they catalyse reactions on substrates within reach. Studies of binding and catalysis have led to a binding- induced allosteric activation model for enzymes, such as SHP-1, whose catalytic activity increases upon recruitment to inhibitory receptors, such as PD-1. However, the impact of molecular reach is poorly understood. Here, we use surface plasmon resonance to measure binding, catalysis, and molecular reach for tethered SHP-1 reactions. We find a molecular reach for SHP-1 (13.0 nm) that is smaller than a maximum stretch estimate (20.4 nm) but larger than an estimate from crystal structure of the active conformation (5.3 nm), suggesting that SHP-1 explores a spectrum of active conformations. The molecular reach confines SHP-1 to a small membrane-proximal volume near its substrates leading membrane recruitment to increase its activity by a 1000-fold increase in concentration with a smaller 2-fold activity increase by PD-1 binding-induced allostery. Lastly, we use mathematical modelling to quantify the degree of co-clustering required for PD-1-SHP-1 complexes to reach their substrates.

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Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation

Cited by 103 publications

References 69 publications

Revisiting the PD-1 pathway

Revisiting the PD-1 pathway

Delicate Role of PD-L1/PD-1 Axis in Blood Vessel Inflammatory Diseases: Current Insight and Future Significance

Determination of the molecular reach of the protein tyrosine phosphatase SHP-1

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