Structural Implications of STAT3 and STAT5 SH2 Domain Mutations
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 o...
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| Format: | Article |
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MDPI AG
2019-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/11/1757 |
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| author | Elvin D. de Araujo Anna Orlova Heidi A. Neubauer Dávid Bajusz Hyuk-Soo Seo Sirano Dhe-Paganon György M. Keserű Richard Moriggl Patrick T. Gunning |
| author_facet | Elvin D. de Araujo Anna Orlova Heidi A. Neubauer Dávid Bajusz Hyuk-Soo Seo Sirano Dhe-Paganon György M. Keserű Richard Moriggl Patrick T. Gunning |
| author_sort | Elvin D. de Araujo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T06:58:04Z |
| format | Article |
| id | doaj.art-6b49a0a114ab4744bd0a2e6db99950db |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T06:58:04Z |
| publishDate | 2019-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6b49a0a114ab4744bd0a2e6db99950db2023-09-02T23:54:11ZengMDPI AGCancers2072-66942019-11-011111175710.3390/cancers11111757cancers11111757Structural Implications of STAT3 and STAT5 SH2 Domain MutationsElvin D. de Araujo0Anna Orlova1Heidi A. Neubauer2Dávid Bajusz3Hyuk-Soo Seo4Sirano Dhe-Paganon5György M. Keserű6Richard Moriggl7Patrick T. Gunning8Centre for Medicinal Chemistry, University of Toronto at Mississauga, Mississauga, ON L5L 1C6, CanadaInstitute of Animal Breeding and Genetics, University of Veterinary Medicine, A-1210 Vienna, AustriaInstitute of Animal Breeding and Genetics, University of Veterinary Medicine, A-1210 Vienna, AustriaMedicinal Chemistry Research Group, Research Center for Natural Sciences, 1117 Budapest, HungaryDepartment of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USAMedicinal Chemistry Research Group, Research Center for Natural Sciences, 1117 Budapest, HungaryInstitute of Animal Breeding and Genetics, University of Veterinary Medicine, A-1210 Vienna, AustriaCentre for Medicinal Chemistry, University of Toronto at Mississauga, Mississauga, ON L5L 1C6, CanadaSrc 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.https://www.mdpi.com/2072-6694/11/11/1757stat3stat5sh2 domainmutationscancerautosomal-dominant hyper ige syndromeinflammatory hepatocellular adenomast-cell large granular lymphocytic leukemiat-cell prolymphocytic leukemiagrowth hormone insensitivity syndrome |
| spellingShingle | Elvin D. de Araujo Anna Orlova Heidi A. Neubauer Dávid Bajusz Hyuk-Soo Seo Sirano Dhe-Paganon György M. Keserű Richard Moriggl Patrick T. Gunning Structural Implications of STAT3 and STAT5 SH2 Domain Mutations Cancers 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 |
| title | Structural Implications of STAT3 and STAT5 SH2 Domain Mutations |
| title_full | Structural Implications of STAT3 and STAT5 SH2 Domain Mutations |
| title_fullStr | Structural Implications of STAT3 and STAT5 SH2 Domain Mutations |
| title_full_unstemmed | Structural Implications of STAT3 and STAT5 SH2 Domain Mutations |
| title_short | Structural Implications of STAT3 and STAT5 SH2 Domain Mutations |
| title_sort | structural implications of stat3 and stat5 sh2 domain mutations |
| topic | 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 |
| url | https://www.mdpi.com/2072-6694/11/11/1757 |
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