Sticking It to Cancer with Molecular Glue for SHP2

Hao, Ran; Tsutsumi, Ryouhei; Araki, Toshiyuki; Neel, Benjamin G.

doi:10.1016/j.ccell.2016.07.010

Cited by 83 publications

(87 citation statements)

References 11 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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“…In addition, none of them have been profiled extensively for offtarget effects against other enzyme families. Furthermore, where in vivo efficacy has been reported, on-target activity has not been demonstrated convincingly [17].…”

Section: Shp-2mentioning

confidence: 99%

“…SHP-2 contains two SH2 domains (N-SH2/CSH2), a catalytic (PTP) domain, and a C-terminal tail with 2 tyrosine phosphorylation sites [17]. SHP-2 binding sites are found in receptor tyrosine kinases (RTKs) and scaffolding adapter proteins, thus this "molecular switch" ensures that SHP-2 is activated only at specific cellular compartments.…”

Section: Shp-2mentioning

confidence: 99%

“…This strong validation of SHP-1, 2 and SHIP as oncology targets has generated considerable interest in the development of small molecule inhibitors as potential therapeutic agents for haematologic malignancies and solid tumours [12,[16][17][18]. Unfortunately, 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 its PTP active site [19], and PTP inhibitor development has sent many pharmaceutical companies to the graveyard in the last decade.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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“…18 All these recent discoveries indicate SHP2 as an attractive target in future anti-cancer therapies. 19,20,21 The structure of SHP2 includes two tandemly-arranged Src homology 2 domains, called N-SH2 and C-SH2, followed by the catalytic PTP domain, and a C-terminal tail with a still poorly characterized function. The SH2 domains are recognition elements that allow SHP2 to bind to signaling partners containing a phosphorylated tyrosine (pY).…”

Section: Introductionmentioning

confidence: 99%

An allosteric interaction controls the activation mechanism of SHP2 tyrosine phosphatase

Anselmi

Hub

2020

Preprint

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SHP2 is a protein tyrosine phosphatase with a key role in multiple signaling pathways, including the RAS-MAPK cascade. Germline mutations in PTPN11, the gene encoding SHP2, occur in 50% of individuals affected by Noonan syndrome, whereas somatic mutations in this gene cause more than 30% of cases of juvenile myelomonocytic leukemia (JMML), and are variably found in other pediatric hematologic malignancies and tumors. Inhibition of the wild-type protein has been recently demonstrated as a novel effective therapeutic strategy for many forms of cancer. Under basal conditions, wild-type SHP2 is inactive because its N-terminal Src homology 2 (N-SH2) domain blocks the active site of the protein tyrosine phosphatase (PTP) domain. Previous work established that binding of a phosphopeptide ligand to the N-SH2 domain causes SHP2 activation by favoring dissociation of the N-SH2 and PTP domains, however the conformational transitions of N-SH2 controlling ligand affinity and PTP dissociation are not well understood. Based on molecular simulations and free-energy calculations, we revealed a 20Å-spanning allosteric network restraining the N-SH2 domain to two distinct states, a SHP2-activating and a stabilizing state. We find that ligand binding is necessary but not sufficient for SHP2 activation, as only ligands selecting for the activating conformation of N-SH2, depending on ligand sequence and binding mode, are predicted to be effective activators. The proposed model of SHP2 activation is further validated by rationalizing modified basal activity and responsiveness to ligand stimulation of N-SH2 variations at residue Tyr 42 . This study provides mechanistic and energetic insight into SHP2 activation and may open novel routes for SHP2 regulation.

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Sticking It to Cancer with Molecular Glue for SHP2

Cited by 83 publications

References 11 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

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

An allosteric interaction controls the activation mechanism of SHP2 tyrosine phosphatase

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