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Structural Implications of STAT3 and STAT5 SH2 Domain Mutations

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Centre for Medicinal Chemistry, University of Toronto at Mississauga, Mississauga, ON L5L 1C6, Canada
2
Department of Chemical & Physical Sciences, University of Toronto at Mississauga, Mississauga, ON L5L 1C6, Canada
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Institute of Animal Breeding and Genetics, University of Veterinary Medicine, A-1210 Vienna, Austria
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Medicinal Chemistry Research Group, Research Center for Natural Sciences, 1117 Budapest, Hungary
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Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
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Department of Biological Chemistry, Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(11), 1757; https://doi.org/10.3390/cancers11111757
Received: 30 September 2019 / Revised: 2 November 2019 / Accepted: 5 November 2019 / Published: 8 November 2019
(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)
Src Homology 2 (SH2) domains arose within metazoan signaling pathways and are involved in protein regulation of multiple pleiotropic cascades. In signal transducer and activator of transcription (STAT) proteins, SH2 domain interactions are critical for molecular activation and nuclear accumulation of phosphorylated STAT dimers to drive transcription. Sequencing analysis of patient samples has revealed the SH2 domain as a hotspot in the mutational landscape of STAT proteins although the functional impact for the vast majority of these mutations remains poorly characterized. Despite several well resolved structures for SH2 domain-containing proteins, structural data regarding the distinctive STAT-type SH2 domain is limited. Here, we review the unique features of STAT-type SH2 domains in the context of all currently reported STAT3 and STAT5 SH2 domain clinical mutations. The genetic volatility of specific regions in the SH2 domain can result in either activating or deactivating mutations at the same site in the domain, underscoring the delicate evolutionary balance of wild type STAT structural motifs in maintaining precise levels of cellular activity. Understanding the molecular and biophysical impact of these disease-associated mutations can uncover convergent mechanisms of action for mutations localized within the STAT SH2 domain to facilitate the development of targeted therapeutic interventions. View Full-Text
Keywords: STAT3; STAT5; SH2 domain; mutations; cancer; autosomal-dominant hyper IgE syndrome; inflammatory hepatocellular adenomas; T-cell large granular lymphocytic leukemia; T-cell prolymphocytic leukemia; growth hormone insensitivity syndrome STAT3; STAT5; SH2 domain; mutations; cancer; autosomal-dominant hyper IgE syndrome; inflammatory hepatocellular adenomas; T-cell large granular lymphocytic leukemia; T-cell prolymphocytic leukemia; growth hormone insensitivity syndrome
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de Araujo, E.D.; Orlova, A.; Neubauer, H.A.; Bajusz, D.; Seo, H.-S.; Dhe-Paganon, S.; Keserű, G.M.; Moriggl, R.; Gunning, P.T. Structural Implications of STAT3 and STAT5 SH2 Domain Mutations. Cancers 2019, 11, 1757.

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