Targeting Protein Tyrosine Phosphatase SHP2 for Therapeutic Intervention

Butterworth, Sam; Overduin, Michael; Barr, Alastair J.

doi:10.4155/fmc.14.88

Cited by 66 publications

(70 citation statements)

References 113 publications

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“…PTPN11 mutations also cause Noonan syndrome and Noonan syndrome with multiple lentigines, two disorders belonging to a family of rare diseases collectively known as RASopathies [Tartaglia 2001;Tartaglia 2004a;Tartaglia 2010]. For all these reasons, SHP2 is an important molecular target for therapies against cancer and rare diseases [Butterworth 2014;Ran 2016, Frankson 2017. At the molecular level, pathogenic mutations of PTPN11 often cause an increase in the binding affinity of the SH2 domains of SHP2, leading to hyper-activated signaling of the Ras/MAPK pathway [Tartaglia 2006;Bocchinfuso 2007;Martinelli 2008;Martinelli 2012].…”

Section: The Sh2 Domain-containing Protein Tyrosine Phosphatasementioning

confidence: 99%

Structural Determinants of Phosphopeptide Binding to the N-Terminal Src Homology 2 Domain of the SHP2 Phosphatase

Anselmi

Calligari

Hub

et al. 2020

Preprint

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ABSTRACTSH2 domain-containing tyrosine phosphatase 2 (SHP2), encoded by PTPN11, plays a fundamental role in the modulation of several signaling pathways. Germline and somatic mutations in PTPN11 are associated with different rare diseases and hematologic malignancies, and recent studies have individuated SHP2 as a central node in oncogenesis and cancer drug resistance. SHP2 structure includes two Src homology 2 domains (N-SH2 and C-SH2) followed by a catalytic protein tyrosine phosphatase (PTP) domain. Under basal conditions, the N-SH2 domain blocks the active site, inhibiting phosphatase activity. Association of the N-SH2 domain with binding partners containing short amino acid motifs comprising a phosphotyrosine residue (pY) leads to N-SH2/PTP dissociation and SHP2 activation. Considering the relevance of SHP2 in signaling and disease and the central role of the N-SH2 domain in its allosteric regulation mechanism, we performed microsecond-long molecular dynamics simulations of the N-SH2 domain complexed to 12 different peptides, to define the structural and dynamical features determining the binding affinity and specificity of the domain. Phosphopeptide residues at position −2 to +5, with respect to pY, have significant interactions with the SH2 domain. In addition to the strong interaction of the pY residue with its conserved binding pocket, the complex is stabilized hydrophobically by insertion of residues +1, +3 and +5 in an apolar groove of the domain, and interaction of residue −2 with both the pY and a protein surface residue. Additional interactions are provided by hydrogen bonds formed by the backbone of residues −1, +1, +2 and +4. Finally, negatively charged residues at position +2 and +4 are involved in electrostatic interactions with two lysines (Lys89 and Lys91) specific of the SHP2 N-SH2 domain. Interestingly, the MD simulations illustrated a previously undescribed conformational flexibility of the domain, involving the core β-sheet and the loop that closes the pY binding pocket.

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Section: The Sh2 Domain-containing Protein Tyrosine Phosphatasementioning

confidence: 99%

Structural Determinants of Phosphopeptide Binding to the N-Terminal Src Homology 2 Domain of the SHP2 Phosphatase

Anselmi

Calligari

Hub

et al. 2020

Preprint

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“…Protein phosphatases have highly conserved residues around catalytic sites, and therefore attaining selectivity has been a formidable challenge. Over the course of last several years, efforts have been made to develop inhibitors of SHP2 for clinical use based on their activity in vitro and in vivo [34]. However, despite promising pre-clinical results, little progress has been made in translating these findings into clinic.…”

Section: Targeting Shp2 In Hematological Malignancymentioning

confidence: 99%

Role of SHP2 in hematopoiesis and leukemogenesis

Pandey¹,

Saxena²,

Kapur

2017

Current Opinion in Hematology

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Purpose of review SH2 domain-containing tyrosine phosphatase 2 (SHP2), encoded by PTPN11 plays an important role in regulating signaling from cell surface receptor tyrosine kinases during normal development as well as oncogenesis. Herein we review recently discovered roles of SHP2 in normal and aberrant hematopoiesis along with novel strategies to target it. Recent findings Cell autonomous role of SHP2 in normal hematopoiesis and leukemogenesis has long been recognized. The review will discuss the newly discovered role of SHP2 in lineage specific differentiation. Recently, a non-cell autonomous role of oncogenic SHP2 has been reported in which activated SHP2 was shown to alter the bone marrow microenvironment resulting in transformation of donor derived normal hematopoietic cells and development of myeloid malignancy. From being considered as an ‘undruggable’ target, recent development of allosteric inhibitor has made it possible to specifically target SHP2 in receptor tyrosine kinase driven malignancies. Summary SHP2 has emerged as an attractive target for therapeutic targeting in hematological malignancies for its cell autonomous and micro-environmental effects. However a better understanding of the role of SHP2 in different hematopoietic lineages and its crosstalk with signaling pathways activated by other genetic lesions is required before the promise is realized in the clinic.

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“…Indeed, SHP2 inhibitors ( Table 2 ) are currently being developed for the treatment of various leukemias and other forms of cancer, 72, 73 where elevated SHP2 activity contributes to oncogenesis. 74, 75 In contrast, inhibition of SHP1, for which no specific inhibitors have been reported, may result in undesirable side effects, given its important negative regulatory role in many survival and growth signaling pathways in hematopoietic cells, 43 and the fact that mice deficient in SHP1 display a severe autoimmune and immunodeficiency syndrome ( motheaten mouse).…”

Section: Classical Ptps In Platelet Signalingmentioning

confidence: 99%

Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy

Tautz

Senis

Oury

et al. 2015

Bioorganic & Medicinal Chemistry

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Arterial thrombosis is the primary cause of most cases of myocardial infarction and stroke, the leading causes of death in the developed world. Platelets, highly specialized cells of the circulatory system, are key contributors to thrombotic events. Antiplatelet drugs, which prevent platelets from aggregating, have been very effective in reducing the mortality and morbidity of these conditions. However, approved antiplatelet therapies have adverse side effects, most notably the increased risk of bleeding. Moreover, there remains a considerable incidence of arterial thrombosis in a subset of patients receiving currently available drugs. Thus, there is a pressing medical need for novel antiplatelet agents with a more favorable safety profile and less patient resistance. The discovery of novel antiplatelet targets is the matter of intense ongoing research. Recent findings demonstrate the potential of targeting key signaling molecules, including kinases and phosphatases, to prevent platelet activation and aggregation. Here, we offer perspectives to targeting members of the protein tyrosine phosphatase (PTP) superfamily, a major class of enzymes in signal transduction. We give an overview of previously identified PTPs in platelet signaling, and discuss their potential as antiplatelet drug targets. We also introduce VHR (DUSP3), a PTP that we recently identified as a major player in platelet biology and thrombosis. We review our data on genetic deletion as well as pharmacological inhibition of VHR, providing proof-of-principle for a novel and potentially safer VHR-based antiplatelet therapy.

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Targeting Protein Tyrosine Phosphatase SHP2 for Therapeutic Intervention

Cited by 66 publications

References 113 publications

Structural Determinants of Phosphopeptide Binding to the N-Terminal Src Homology 2 Domain of the SHP2 Phosphatase

Structural Determinants of Phosphopeptide Binding to the N-Terminal Src Homology 2 Domain of the SHP2 Phosphatase

Role of SHP2 in hematopoiesis and leukemogenesis

Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy

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