Protein tyrosine phosphatase SHP2/PTPN11 mistargeting as a consequence of SH2-domain point mutations associated with Noonan Syndrome and leukemia

Müller, Pia; Rigbolt, Kristoffer T.G.; Paterok, Dirk; Piehler, Jacob; Vanselow, Jens T.; Lasonder, Edwin; Andersen, Jens S.; Schaper, Fred; Sobota, Radoslaw M.

doi:10.1016/j.jprot.2013.04.005

Cited by 19 publications

(23 citation statements)

References 60 publications

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“…Particularly in case of NS and LS, two syndromes that are associated with expression of mutant Shp2, a protein-tyrosine phosphatase. Recently, a MS based approach was used to identify proteins that were affected by the altered binding properties of NS and leukemia associated Shp2 [35]. Although highly informative, these experiments were performed using the tandem SH2 of Shp2 expressed in cells.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Fer and Src (an important Shp2 interacting protein) share many substrates, including cortactin [41], [49]. Disease associated Shp2 exhibits altered dynamics and binding properties [35]–[37]. Mutant Shp2 may quench binding proteins that are normally required for full activation of Fer kinase, resulting in reduced tyrosine phosphorylation of Fer upon expression of NS and LS Shp2.…”

Section: Discussionmentioning

confidence: 99%

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Phosphoproteomics-Mediated Identification of Fer Kinase as a Target of Mutant Shp2 in Noonan and LEOPARD Syndrome

et al. 2014

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Noonan syndrome (NS) and LEOPARD syndrome (LS) cause congenital afflictions such as short stature, hypertelorism and heart defects. More than 50% of NS and almost all of LS cases are caused by activating and inactivating mutations of the phosphatase Shp2, respectively. How these biochemically opposing mutations lead to similar clinical outcomes is not clear. Using zebrafish models of NS and LS and mass spectrometry-based phosphotyrosine proteomics, we identified a down-regulated peptide of Fer kinase in both NS and LS. Further investigation showed a role for Fer during development, where morpholino-based knockdown caused craniofacial defects, heart edema and short stature. During gastrulation, loss of Fer caused convergence and extension defects without affecting cell fate. Moreover, Fer knockdown cooperated with NS and LS, but not wild type Shp2 to induce developmental defects, suggesting a role for Fer in the pathogenesis of both NS and LS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phosphoproteomics-Mediated Identification of Fer Kinase as a Target of Mutant Shp2 in Noonan and LEOPARD Syndrome

et al. 2014

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“…p.Thr42Ala might gain function to promote dissociation of N‐SH2/PTP binding through increased phosphopeptide‐binding affinity 34, 35. RAS‐MAPK hyperactivation is implicated in JMML/MPD in NS 3.…”

Section: Discussionmentioning

confidence: 99%

“…33 p.Thr42Ala might gain function to promote dissociation of N-SH2/PTP binding through increased phosphopeptide-binding affinity. 34,35 RAS-MAPK hyperactivation is implicated in JMML/MPD in NS. 3 In contrast, HCM in LEOPARD syndrome (LS) is associated with loss-of-function mutations in PTPN11, which result in enhanced PI3K-AKT and reduced RAS-MAPK pathway activities.…”

Section: Discussionmentioning

confidence: 99%

Co‐occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death

Tamura

Uemura

Matsubara

et al. 2018

Clinical Case Reports

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“…PTPs regulate several cellular processes, including cell growth, cellular differentiation, mitotic cycles and oncogenic transformation (8,9). PTPs also regulate the phosphorylation state of numerous signalling molecules with PTKs, including the MAP kinase family and signal transducer and activator of transcription family proteins (25,26). In recent years, there has been expanding interest in the role of SHP2 in the genesis, development and prognosis of thyroid cancer.…”

Section: Discussionmentioning

confidence: 99%

Expression and clinical significance of tyrosine phosphatase SHP2 in thyroid carcinoma

Chi-min

et al. 2015

Oncology Letters

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Abstract. Protein-tyrosine phosphatase SHP2 is encoded by the gene PTPN11. SHP2 is hypothesized to have a critical role in cancer, via the activation of mutations that have been detected in several types of leukaemia and in certain solid tumours, including liver, breast, gastric and cervical cancer. However, to the best of our knowledge, there have been no previous reports evaluating the significance of SHP2 expression in thyroid cancer. The present study evaluated SHP2 expression in 65 thyroid cancer specimens, 40 specimens of self-matched adjacent peritumour tissues and 40 specimens of normal thyroid tissue, using immunohistochemical and western blot analyses with an anti-SHP2 antibody. Western blotting was also used to assess SHP2 expression in thyroid cancer cell lines (SW579, IHH-4, FTC-133, TPC-1, DRO, TA-K, and ML-1) and Nthy-ori3-1 normal thyroid cells. In addition, SHP2 antisense oligonucleotides were used to block SHP2 expression in SW579 cells, and growth inhibition assays were conducted. Increased SHP2 expression was detected in the tumour tissues compared with that of the normal thyroid tissues (P<0.05). SHP2 expression was significantly correlated with poor tumour differentiation (P<0.05), late TNM stage (P<0.05) and lymph node metastasis (P<0.05), suggesting that SHP2 may represent a potential target for thyroid cancer therapy.

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Protein tyrosine phosphatase SHP2/PTPN11 mistargeting as a consequence of SH2-domain point mutations associated with Noonan Syndrome and leukemia

Cited by 19 publications

References 60 publications

Phosphoproteomics-Mediated Identification of Fer Kinase as a Target of Mutant Shp2 in Noonan and LEOPARD Syndrome

Phosphoproteomics-Mediated Identification of Fer Kinase as a Target of Mutant Shp2 in Noonan and LEOPARD Syndrome

Co‐occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death

Expression and clinical significance of tyrosine phosphatase SHP2 in thyroid carcinoma

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