Antagonism between binding site affinity and conformational dynamics tunes alternative cis-interactions within Shp2

Sun, Jie; Lu, Shaoying; Ouyang, Mingxing; Lin, Li-Jung; Yang, Zhuo; Liu, Bo; Chien, Shu; Neel, Benjamin G.; Wang, Yingxiao

doi:10.1038/ncomms3037

Cited by 37 publications

(34 citation statements)

References 44 publications

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“…Of the 147,111 Immunochip SNPs that passed quality control analyses, only 30% begin or end a CpG site. Although this is a novel SLE association, GRB2 reportedly regulates SHP2 activity2728, a potential contributor to SLE pathogenesis29.…”

Section: Resultsmentioning

confidence: 97%

Transancestral mapping and genetic load in systemic lupus erythematosus

et al. 2017

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Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10−8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

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Section: Resultsmentioning

confidence: 97%

Transancestral mapping and genetic load in systemic lupus erythematosus

et al. 2017

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“…3 and S1), despite reports indicating that PTPN11-Y580 is essential for sustained ERK phosphorylation [24,25]. It has been shown that ligand binding to either phosphorylated Y542 or Y580 play regulatory roles for PTPN11 activity [26], and thus for growth factor-mediated signal transduction through PTPN11 [5,27]. The results were similar but not identical to a cell line transfected with the PDGFRB-Val665Ala variant found in patients with classical Penttinen syndrome, where constitutive PLCγ and STAT3 but not AKT phosphorylation was found [12].…”

Section: Discussionmentioning

confidence: 95%

A tyrosine kinase-activating variant Asn666Ser in PDGFRB causes a progeria-like condition in the severe end of Penttinen syndrome

et al. 2018

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Missense variants located to the "molecular brake" in the tyrosine kinase hinge region of platelet-derived growth factor receptor-β, encoded by PFGFRB, can cause Penttinen-type (Val665Ala) and Penttinen-like (Asn666His) premature ageing syndromes, as well as infantile myofibromatosis (Asn666Lys and Pro660Thr). We have found the same de novo PDGFRB c.1997A>G p.(Asn666Ser) variants in two patients with lipodystrophy, acro-osteolysis and severely reduced vision due to corneal neovascularisation, reminiscent of a severe form of Penttinen syndrome with more pronounced connective tissue destruction. In line with this phenotype, patient skin fibroblasts were prone to apoptosis. Both in patient fibroblasts and stably transduced HeLa and HEK293 cells, autophosphorylation of PDGFRβ was observed, as well as increased phosphorylation of downstream signalling proteins such as STAT1, PLCγ1, PTPN11/SHP2-Tyr580 and AKT. Phosphorylation of MAPK3 (ERK1) and PTPN11/SHP2-Tyr542 appeared unaffected. This suggests that this missense change not only weakens tyrosine kinase autoinhibition, but also influences substrate binding, as both PTPN11 tyrosines (Tyr542 and Tyr580) usually are phosphorylated upon PDGFR activation. Imatinib was a strong inhibitor of phosphorylation of all these targets, suggesting an option for precision medicine based treatment.

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“…4C). Phosphorylated tyrosines in the C-terminal tail of SHP2 are proposed to bind GRB2 and may modulate SOS1 plasma membrane localization via the well-established GRB2/SOS1 association 34,35 . We would expect potential disruption of this interaction by RMC-4550 to be bypassed by SOS-F, which is targeted to the membrane independently of GRB2 association.…”

Section: Inhibition Of Shp2-dependent Ras-gtp Loading Can Be Rescuedmentioning

confidence: 99%

Efficacy of SHP2 phosphatase inhibition in cancers with nucleotide-cycling oncogenic RAS, RAS-GTP dependent oncogenic BRAF and NF1 loss

Nichols

Haderk

Stahlhut

et al. 2017

Preprint

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Oncogenic alterations in the RAS-RAF-MEK-ERK pathway, including mutant forms of KRAS, BRAF, and loss of the tumor suppressor and RAS GTPase-activating protein (GAP) NF1, drive the growth of a wide spectrum of human cancers. While BRAF and MEK inhibitors are effective in many patients with oncogenic BRAF V600E, there are no effective targeted therapies for individuals with cancers driven by other pathway alterations, including oncogenic KRAS, non-V600E BRAF, and NF1 loss. Here, we show that targeting the PTPN11/SHP2 phosphatase with a novel small molecule allosteric inhibitor is effective against cancers bearing nucleotide-cycling oncogenic RAS (e.g. KRAS G12C), RAS-GTP dependent oncogenic BRAF (e.g. class 3 BRAF mutants), or NF1 loss in multiple preclinical models in vitro and in vivo. SHP2 inhibition suppressed the levels of RAS-GTP and phosphorylated ERK in these models and induced growth inhibition. Expression of a constitutively active mutant of the RAS guanine nucleotide exchange factor (GEF) SOS1 rescued cells from the effects of SHP2 inhibition, suggesting that SHP2 blockade decreases oncogenic RAS-RAF-MEK-ERK signaling by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS activation and downstream signaling in cancers with nucleotide-cycling oncogenic RAS, RAS-GTP dependent oncogenic BRAF, and NF1 loss. SHP2 inhibition thus represents a rational, biomarker-driven therapeutic strategy to be tested in patients with cancers of diverse origins bearing these oncogenic drivers and for which current treatments are largely ineffective.Keywords: PTPN11, KRAS, G12C, BRAF, NF1, lung cancer INTRODUCTION RAS proteins are small GTPases that operate as molecular switches. When GTP-bound, RAS can engage downstream effector proteins, including RAF, to activate the MEK-ERK (MAPK) pathway and promote cellular proliferation 1 . Activation of receptor tyrosine kinases (RTKs) leads to activation of RAS guanine nucleotide exchange factors (GEFs), such as son of sevenless homolog 1 (SOS1), to promote GTP loading of RAS and signaling, while RAS GTPase-activating proteins (GAPs) stimulate GTP hydrolysis and terminate RAS activation and signaling 2 . This homeostatic GEF/GAP cycle is disrupted by oncogenic mutations in RAS and upstream components of the pathway, and can also be bypassed by mutations in downstream components.

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Antagonism between binding site affinity and conformational dynamics tunes alternative cis-interactions within Shp2

Cited by 37 publications

References 44 publications

Transancestral mapping and genetic load in systemic lupus erythematosus

Transancestral mapping and genetic load in systemic lupus erythematosus

A tyrosine kinase-activating variant Asn666Ser in PDGFRB causes a progeria-like condition in the severe end of Penttinen syndrome

Efficacy of SHP2 phosphatase inhibition in cancers with nucleotide-cycling oncogenic RAS, RAS-GTP dependent oncogenic BRAF and NF1 loss

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