Structural Requirements for Signal Transducer and Activator of Transcription 3 Binding to Phosphotyrosine Ligands Containing the YXXQ Motif

Shao, Huang; Xu, Xuejun; Mastrangèlo, Mary Ann; Ning, Jianguo; Cook, Richard G.; Legge, Glen B.; Tweardy, David J.

doi:10.1074/jbc.m314037200

Cited by 46 publications

(50 citation statements)

References 43 publications

(38 reference statements)

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“…Similar computational analysis has been applied in the development of inhibitors of Stat3 and other proteins (14,15). The docking pose of S3I-201 suggests that its aminosalicylic moiety mimics the phenylphosphate group of the PpYLKT motif.…”

Section: Discussionmentioning

confidence: 99%

“…Stat3 dimerization relies on the reciprocal binding of the SH2 domain of one monomer to the Pro-pTyr-Leu-Lys-Thr-Lys sequence of the other Stat3 monomer. To pursue the development of inhibitors of Stat3 signaling, key structural information gleaned from the x-ray crystal structure of the Stat3␤ homodimer (13) was used in the computational modeling and automated docking of small molecules into the SH2 domain of a Stat3 monomer, relative to the bound native pTyr peptide, to identify binders of the Stat3 SH2 domain, and potentially disruptors of Stat3⅐Stat3 dimers (14,15).…”

mentioning

confidence: 99%

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Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity

Siddiquee

Zhang

Guida

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

685

669

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P roteins of the STAT (signal transducer and activator of transcription) family are activated in response to cytokines and growth factors and promote proliferation, survival, and other biological processes (1-3). STATs are activated by phosphorylation of a critical tyrosine residue, which is mediated by growth factor receptor tyrosine kinases, Janus kinases, or the Src family kinases. Upon tyrosine phosphorylation, dimers of STATs formed between two phosphorylated monomers translocate to the nucleus, bind to specific DNA-response elements in the promoters of target genes, and induce gene expression. Aberrant activity of one of the family members, Stat3, contributes to carcinogenesis and tumor progression by up-regulating gene expression and promoting dysregulated growth, survival, and angiogenesis and modulating immune responses (2-9).As a critical step in STAT activation (10), the dimerization between two STAT monomers presents an attractive target to abolish Stat3 DNA-binding and transcriptional activity and to inhibit Stat3 biological functions (11, 12). Stat3 dimerization relies on the reciprocal binding of the SH2 domain of one monomer to the Pro-pTyr-Leu-Lys-Thr-Lys sequence of the other Stat3 monomer. To pursue the development of inhibitors of Stat3 signaling, key structural information gleaned from the x-ray crystal structure of the Stat3␤ homodimer (13) was used in the computational modeling and automated docking of small molecules into the SH2 domain of a Stat3 monomer, relative to the bound native pTyr peptide, to identify binders of the Stat3 SH2 domain, and potentially disruptors of Stat3⅐Stat3 dimers (14, 15).Structure-based high-throughput virtual screening of the National Cancer Institute (NCI) chemical libraries identified the high-scoring compound NSC 74859 (resynthesized as a pure sample and named S3I-201), which selectively inhibits Stat3 DNA-binding activity in vitro with an IC 50 value of 86 Ϯ 33 M. Furthermore, S3I-201 induces growth inhibition and apoptosis of malignant cells in part by constitutively inhibiting active Stat3 and induces human breast tumor regression in xenograft models. ResultsComputational Modeling and Virtual Screening. Our computational modeling and virtual screening study used the GLIDE (Grid-based Ligand Docking from Energetics) software (16, 17) (available from Schrödinger, Portland, OR) for the docking simulations and relied on the x-ray crystal structure of the Stat3␤ homodimer bound to DNA (13) determined at 2.25-Å resolution (1BG1 in the Protein Data Bank). For the virtual screening, DNA was removed and only one of the two monomers was used (see Fig. 1). To validate the docking approach, the native pTyr (pY) peptide, APpYLKT, was extracted from the crystal structure of one of the monomers and docked to the other monomer, whereby GLIDE produced a docking mode that closely resembled the x-ray crystal structure (data not shown). Three-dimensional structures of compounds from the NCI's chemical libraries were downloaded from the NCI Developmental Therapeutics Progra...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity

Siddiquee

Zhang

Guida

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

685

669

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“…3G). Examination of the protein sequence of PTPRD revealed that the cytoplasmic domain possesses 3 consensus STAT3 binding motifs (PYXXQ) (28). Moreover, knockdown of PTPRD using siRNA in both HEK 293T cells and human astrocytes results in an increase in STAT3 phosphorylation (Fig.…”

Section: Ptprd Is Mutated In Gbm and Other Human Malignanciesmentioning

confidence: 99%

The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers

Veeriah¹,

Brennan²,

Meng³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

255

308

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Tyrosine phosphorylation plays a critical role in regulating cellular function and is a central feature in signaling cascades involved in oncogenesis. The regulation of tyrosine phosphorylation is coordinately controlled by kinases and phosphatases (PTPs). Whereas activation of tyrosine kinases has been shown to play vital roles in tumor development, the role of PTPs is much less well defined. Here, we show that the receptor protein tyrosine phosphatase delta (PTPRD) is frequently inactivated in glioblastoma multiforme (GBM), a deadly primary neoplasm of the brain. PTPRD is a target of deletion in GBM, often via focal intragenic loss. In GBM tumors that do not possess deletions in PTPRD, the gene is frequently subject to cancer-specific epigenetic silencing via promoter CpG island hypermethylation (37%). Sequencing of the PTPRD gene in GBM and other primary human tumors revealed that the gene is mutated in 6% of GBMs, 13% of head and neck squamous cell carcinomas, and in 9% of lung cancers. These mutations were deleterious. In total, PTPRD inactivation occurs in >50% of GBM tumors, and loss of expression predicts for poor prognosis in glioma patients. Wild-type PTPRD inhibits the growth of GBM and other tumor cells, an effect not observed with PTPRD alleles harboring cancer-specific mutations. Human astrocytes lacking PTPRD exhibited increased growth. PTPRD was found to dephosphorylate the oncoprotein STAT3. These results implicate PTPRD as a tumor suppressor on chromosome 9p that is involved in the development of GBMs and multiple human cancers. glioblastoma multiforme ͉ methylation ͉ mutation L oss of tumor suppressor function leads to the initiation and progression of cancer (1, 2). Inactivation of tumor suppressor genes can result from both genetic mechanisms such as mutation and deletion or epigenetic mechanisms such as DNA hypermethylation (3, 4). Identification of these genes has provided insight into the biological processes underlying oncogenesis, but the key tumor suppressors in many cancers, such as glioblastoma multiforme (GBM), remain poorly defined.We previously identified the receptor protein tyrosine phosphatase delta (PTPRD) as a gene that predicts for poor prognosis in breast and colon cancer (4). PTPRD is a member of the highly conserved family of receptor protein tyrosine phosphatases (PTPs), several members of which have been implicated in tumorigenesis (5). The gene encodes a transmembrane protein with a cytoplasmic tyrosine phosphatase domain. The PTPRD gene is located within an area of the genome, chromosome 9p, found to be frequently lost in neuroblastoma, gliomas, lung cancer, and other malignancies (6-9). Some deletions of PTPRD have been noted in several of these studies. However, its close proximity to CDKN2A on chromosome 9p has complicated interpretations. In addition, in independent work during the course of our investigations, PTPRD mutations have been detected in a lung cancer genome study, although no functional validation of the alterations is noted (10-12). Together with thes...

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“…In addition to Lck, coprecipitation of phosphorylated STAT1 and STAT3 with Lck and Tip-C484 was reported (50). A YXPQ motif of Tip (Y72; equivalent to Y114 of C488) conforms to a putative consensus binding site for STAT factors (62). Tyrosine 72 phosphorylation was required for STAT binding and transcription activation (33).…”

mentioning

confidence: 99%

T-Cell Growth Transformation by Herpesvirus Saimiri Is Independent of STAT3 Activation

Heck

Lengenfelder

Schmidt

et al. 2005

J Virol

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Signal transducers and activators of transcription (STATs) are latent cytoplasmic transcription factors that were originally discovered as key mediators of cytokine signaling. They are involved in signaling by the interleukin-6 (IL-6) family cytokines, the IL-2 family cytokines, and numerous growth factors, including epidermal growth factor, platelet-derived growth factor, and colony-stimulating factor 1. Latent inactive STATs reside in the cytoplasm; in response to receptor activation, they are recruited to a receptor where they are tyrosine phosphorylated by receptor tyrosine kinases (RTK) or receptor-associated tyrosine kinases, such as JAK or Trk kinases (reviewed in references 36, 42, 46, and 48). Active STAT dimers are then formed via the reciprocal interaction between the SH2 domain of one monomer and the phosphorylated tyrosine of the other. Activated dimers translocate to the nucleus, where they bind to specific DNA response elements in the promoters of target genes and activate transcription. Furthermore, various oncoproteins can activate specific STAT molecules (especially STAT3 and STAT5) (8,15), and inappropriate STAT activation directly contributes to oncogenesis by stimulating cell proliferation and preventing apoptosis. Constitutive activation of several STATs was frequently detected in a wide range of human cell lines and primary tumors, including lymphoid malignancies (lymphomas, leukemias, and multiple myelomas) (30,63,67). Constitutively activated mutant STAT3 and STAT5 proteins have been shown to possess transforming properties and to be strongly associated with tumor development and progression (7, 9).

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Structural Requirements for Signal Transducer and Activator of Transcription 3 Binding to Phosphotyrosine Ligands Containing the YXXQ Motif

Cited by 46 publications

References 43 publications

Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity

Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity

The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers

T-Cell Growth Transformation by Herpesvirus Saimiri Is Independent of STAT3 Activation

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