Shp1 function in myeloid cells

Abram, Clare L.; Lowell, Clifford A.

doi:10.1189/jlb.2mr0317-105r

Cited by 73 publications

(76 citation statements)

References 186 publications

(246 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 (Shp1) is a potential immunotherapeutic target ( 7 , 8 ). Shp1 is broadly expressed in the hematopoietic compartment and acts as a negative regulator of signaling in both innate and adaptive immune cells ( 9 , 10 ). Thus, alterations in Shp1 have the potential to impact an anti-tumor immune response in several different ways.…”

Section: Introductionmentioning

confidence: 99%

“…Shp1 exerts its inhibitory signaling function by binding to phosphorylated immunoreceptor tyrosine-based inhibitory motifs (ITIMs) on a variety of immunoreceptors. Upon binding and activation, Shp1 dephosphorylates its substrates, thereby transducing inhibitory signals that restrict immune cell function ( 9 , 10 ). Consistent with this, mouse models with spontaneous mutations in the gene encoding Shp1, Ptpn6 , that affect its expression or function develop an inflammatory/autoimmune disease associated with hyperactivation of multiple types of immune cells.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Shp1 Loss Enhances Macrophage Effector Function and Promotes Anti-Tumor Immunity

et al. 2020

Self Cite

View full text Add to dashboard Cite

Shp1, encoded by the gene Ptpn6 , is a protein tyrosine phosphatase that transduces inhibitory signals downstream of immunoreceptors in many immune cell types. Blocking Shp1 activity represents an exciting potential immunotherapeutic strategy for the treatment of cancer, as Shp1 inhibition would be predicted to unleash both innate and adaptive immunity against tumor cells. Antibodies blocking the interaction between CD47 on tumor cells and SIRPα on macrophages enhance macrophage phagocytosis, show efficacy in preclinical tumor models, and are being evaluated in the clinic. Here we found that Shp1 bound to phosphorylated peptide sequences derived from SIRPα and transduced the anti-phagocytic signal, as Shp1 loss in mouse bone marrow-derived macrophages increased phagocytosis of tumor cells in vitro . We also generated a novel mouse model to evaluate the impact of global, inducible Ptpn6 deletion on anti-tumor immunity. We found that inducible Shp1 loss drove an inflammatory disease in mice that was phenotypically similar to that seen when Ptpn6 is knocked out from birth. This indicates that acute perturbation of Shp1 in vivo could drive hyperactivation of immune cells, which could be therapeutically beneficial, though at the risk of potential toxicity. In this model, we found that Shp1 loss led to robust anti-tumor immunity against two immune-rich syngeneic tumor models that are moderately inflamed though not responsive to checkpoint inhibitors, MC38 and E0771. Shp1 loss did not promote anti-tumor activity in the non-inflamed B16F10 model. The observed activity in MC38 and E0771 tumors was likely due to effects of both innate and adaptive immune cells. Following Shp1 deletion, we observed increases in intratumoral myeloid cells in both models, which was more striking in E0771 tumors. E0771 tumors also contained an increased ratio of effector to regulatory T cells following Shp1 loss. This was not observed for MC38 tumors, though we did find increased levels of IFNγ, a cytokine produced by effector T cells, in these tumors. Overall, our preclinical data suggested that targeting Shp1 may be an attractive therapeutic strategy for boosting the immune response to cancer via a mechanism involving both innate and adaptive leukocytes.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Shp1 Loss Enhances Macrophage Effector Function and Promotes Anti-Tumor Immunity

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…27 SHP-1 contains two Src homology (SH)2 domains and a PTP domain and binds to immunoreceptor tyrosine-based inhibition motif-containing proteins, including FcRIIb, carcinoembryonic antigen cell adhesion molecule-1 (CD66a), and platelet and endothelial cell adhesion molecule-1 (CD31) to serve as negative regulator in multiple immune signaling pathways. 28 SHP-1 deficient mice (Ptpn6 me-v/me-v ) display spontaneous and severe inflammatory and autoimmune diseases, indicating that SHP-1 is a key regulator of immune cell function. Our previous results showed that SHP-1 suppresses NF-κB and MAPK signaling transduction in response to infection with enterohemorrhagic Escherichia coli by inhibiting K63-linked polyubiquitination of transforming growth factor beta-activated kinase 1.…”

Section: Introductionmentioning

confidence: 99%

SHP‐1 suppresses the antiviral innate immune response by targeting TRAF3

Hao

et al. 2020

FASEB j.

View full text Add to dashboard Cite

Type I interferons play a pivotal role in innate immune response to virus infection. The protein tyrosine phosphatase SHP‐1 was reported to function as a negative regulator of inflammatory cytokine production by inhibiting activation of NF‐κB and MAPKs during bacterial infection, however, the role of SHP‐1 in regulating type I interferons remains unknown. Here, we demonstrated that knockout or knockdown of SHP‐1 in macrophages promoted both HSV‐1‐ and VSV‐induced antiviral immune response. Conversely, overexpression of SHP‐1 in L929 cells suppressed the HSV‐1‐ and VSV‐induced immune response; suppression was directly dependent on phosphatase activity. We identified a direct interaction between SHP‐1 and TRAF3; the association between these two proteins resulted in diminished recruitment of CK1ε to TRAF3 and inhibited its K63‐linked ubiquitination; SHP‐1 inhibited K63‐linked ubiquitination of TRAF3 by promoting dephosphorylation at Tyr116 and Tyr446. Taken together, our results identify SHP‐1 as a negative regulator of antiviral immunity and suggest that SHP‐1 may be a target for intervention in acute virus infection.

show abstract

“…SHP-1 is expressed by all mature haematopoietic lineages and at low levels (different isoforms) by endothelial cells [10,21]. SHP-1 consists of 3 domains; the N-terminal Src homology-2 (SH2) domain, the C-terminal SH2 domain, and the C-terminal catalytic PTP domain [22], and maximal phosphatase activity is achieved only when both SH2 domains are engaged.…”

Section: Shp-1 2 Pathways: Molecular Biologymentioning

confidence: 99%

“…Although a PTP was traditionally thought to inactivate kinases and to serve as a negative regulator of cell functions, SHP-1, 2 have been shown to promote cell growth and act by both upregulating positive signaling pathways [8] and by downregulating negative signaling pathways [9]. SHP-1 is expressed widely throughout the haematopoietic system and has been shown to impact a multitude of cell signaling pathways [10]. In addition, SHP-2 contributes to the progression of a number of cancer types including leukaemias as well as gastric and breast cancers.…”

Section: Introductionmentioning

confidence: 99%

Targeting SHP-1, 2 and SHIP Pathways: A Novel Strategy for Cancer Treatment?

et al. 2018

View full text Add to dashboard Cite

Well-balanced levels of tyrosine phosphorylation, maintained by the reversible and coordinated actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), are critical for a wide range of cellular processes including growth, diﬀerentiation, metabolism, migration, and survival. Aberrant tyrosine phosphorylation, as a result of a perturbed balance between the activities of PTKs and PTPs, is linked to the pathogenesis of numerous human diseases, including cancer, suggesting that PTPs may be innovative molecular targets for cancer treatment. Two PTPs that have an important inhibitory role in haematopoietic cells are SHP-1 and SHP-2. SHP-1, 2 promote cell growth and act by both upregulating positive signaling pathways and by downregulating negative signaling pathways. SHIP is another inhibitory phosphatase that is specific for the inositol phospholipid phosphatidylinositol-3,4,5-trisphosphate (PIP3). SHIP acts as a negative regulator of immune response by hydrolysing PIP3, and SHIP deficiency results in myeloproliferation and B-cell lymphoma in mice. The validation of SHP-1, 2 and SHIP as oncology targets has generated interest in the development of inhibitors as potential therapeutic agents for cancers; however, SHP-1, 2 and SHIP have proven to be an extremely diﬃcult target for drug discovery, primarily due to the highly conserved and positively charged nature of their PTP active site, and many PTP inhibitors lack either appropriate selectivity or membrane permeability. To overcome these caveats, novel techniques have been employed to synthesise new inhibitors that specifically attenuate the PTP-dependent signaling inside the cell and amongst them; some are already in clinical development which are discussed in this review.

show abstract

Shp1 function in myeloid cells

Cited by 73 publications

References 186 publications

Shp1 Loss Enhances Macrophage Effector Function and Promotes Anti-Tumor Immunity

Shp1 Loss Enhances Macrophage Effector Function and Promotes Anti-Tumor Immunity

SHP‐1 suppresses the antiviral innate immune response by targeting TRAF3

Targeting SHP-1, 2 and SHIP Pathways: A Novel Strategy for Cancer Treatment?

Contact Info

Product

Resources

About