WW and SH3 domains, two different scaffolds to recognize proline‐rich ligands

Macias, María J.; Wiesner, Silke; Sudol, Marius

doi:10.1016/s0014-5793(01)03290-2

Cited by 437 publications

(418 citation statements)

References 42 publications

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“…To find out whether the PPxY motif is critical in the activation of EGR-1, EGR-1 (Y240A) mutant was constructed. Aromatic amino acid residue (Y235) present at the N terminus of the PPxY motifs, which is a crucial determinant of the WW domain-binding activity, was also mutated (Macias et al, 2002). Both the mutations (Y235,240A) lead to a decrease in the EBS-CAT reporter activity in PC3 cells, suggesting that this motif is required for maximal transcriptional activation of EGR-1 (Figure 4b).…”

Section: Egr-1 Induces the Expression Of Baxmentioning

confidence: 99%

EGR-1 forms a complex with YAP-1 and upregulates Bax expression in irradiated prostate carcinoma cells

et al. 2009

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In this study, we investigated the functional role of early growth response-1 (Egr1 gene) in the regulation of radiation-induced clonogenic inhibition and apoptosis in p53 wild-type and mutant prostate cancer cells 22Rv1 and DU145, respectively. 22Rv1 cells were more sensitive to irradiation compared with DU145 cells, and the sensitivity was enhanced by overexpression of EGR-1 in both cells. Dominant-negative EGR-1 mutant (dnEGR-1) or repressor of EGR-1, NGFIA binding protein 1 (NAB1), increased radioresistance of these cells. Significant activation of caspases 3 and 9 and Bcl2-associated X (Bax) with increased poly(ADP-ribose) polymerase (PARP) cleavage and cytochrome c release was observed in radiation-exposed EGR-1 overexpressing cells. Gel shift analysis and chloramphenicol acetyl transferase (CAT) reporter assays indicate that EGR-1 transactivates the promoter of the Bax gene. Interaction of EGR-1 and Yes kinase-associated protein 1 (YAP-1) through the WW domain of YAP-1 enhances the transcriptional activity of EGR-1 on the Bax promoter as shown by chromatin immunoprecipitation and reporter assays. Irradiation of PC3 cell xenografts that were treated with adenoviral EGR-1 showed significant regression in tumor volume. These findings establish the radiation-induced pro-apoptotic action of EGR-1, in a p53-independent manner, by directly transactivating Bax, and prove that alters the B-cell CLL/ lymphoma 2 (Bcl-2)/Bax ratio as one of the mechanisms resulting in significant activation of caspases, leading to cell death through the novel interaction of EGR-1 with YAP-1.

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Section: Egr-1 Induces the Expression Of Baxmentioning

confidence: 99%

EGR-1 forms a complex with YAP-1 and upregulates Bax expression in irradiated prostate carcinoma cells

et al. 2009

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“…Therefore, the WW domain of PQBP1 is versatile and belongs to those domains that show ligand predilections of Class I, II, and III WW domains (17,36,37). From 1895 PPXY peptides probed with the WT WW domain of PQBP1 (Fig.…”

Section: Binding Profiles Of the Mutated And Wt Ww Domains Onmentioning

confidence: 99%

Y65C Missense Mutation in the WW Domain of the Golabi-Ito-Hall Syndrome Protein PQBP1 Affects Its Binding Activity and Deregulates Pre-mRNA Splicing

Tapia

Nicolaescu

McDonald

et al. 2010

Journal of Biological Chemistry

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The PQBP1 (polyglutamine tract-binding protein 1) gene encodes a nuclear protein that regulates pre-mRNA splicing and transcription. Mutations in the PQBP1 gene were reported in several X chromosome-linked mental retardation disorders including Golabi-Ito-Hall syndrome. The missense mutation that causes this syndrome is unique among other PQBP1 mutations reported to date because it maps within a functional domain of PQBP1, known as the WW domain. The mutation substitutes tyrosine 65 with cysteine and is located within the conserved core of aromatic amino acids of the domain. We show here that the binding property of the Y65C-mutated WW domain and the full-length mutant protein toward its cognate proline-rich ligands was diminished. Furthermore, in GolabiIto-Hall-derived lymphoblasts we showed that the complex between PQBP1-Y65C and WBP11 (WW domain-binding protein 11) splicing factor was compromised. In these cells a substantial decrease in pre-mRNA splicing efficiency was detected. Our study points to the critical role of the WW domain in the function of the PQBP1 protein and provides an insight into the molecular mechanism that underlies the X chromosome-linked mental retardation entities classified globally as Renpenning syndrome.

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“…The best known examples of proline-binding activity are the canonical PXXP peptides that interact with most SH3 domains, and short sequences like the P 221 YAQP 225 in the Crk linker which, when phosphorylated on tyrosine, bind to SH2 domains. Proline residues in linker/connector regions have also been shown to be inhibitors in cis of some kinases (Macias et al, 2002). For example, in Hck, the SH3 folds over and interacts intramolecularly with a small proline-containing region, blocking the kinase domain (Sicheri et al, 1997).…”

Section: Contributions Of the Linker (Aa 190-238) And The Crk-sh3-c Tmentioning

confidence: 99%

Transactivation of Abl by the Crk II adapter protein requires a PNAY sequence in the Crk C-terminal SH3 domain

et al. 2005

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To gain a better understanding of how Crk II regulates the function of the Abl tyrosine kinase, we explored the function of the C-terminal linker and SH3 domain, a region of Crk II that is still poorly understood. Molecular modeling, tryptophan fluorescence, and covariation sequence alignment indicate that the Crk-SH3-C has a unique binding groove and RT loop not observed in typical SH3 domains. Based on these models, we made a series of mutations in the linker and in residues predicted to destabilize the putative binding pocket and RT loop. In Abl transactivation assays, Y222F and P225A mutations in the linker resulted in strong transactivation of Abl by Crk II. However, mutations predicted to be at the surface of the Crk SH3-C were not activators of Abl. Interestingly, combinations of activating mutations of Crk II with mutations in the highly conserved PNAY sequence in the SH3-C inactivated the activating mutations, suggesting that the SH3-C is necessary for activation. Our data provide insight into the role of highly conserved residues in the Crk-SH3-C, suggesting a mechanism for how the linker and the Crk-SH3-C function in the transactivation of the Abl tyrosine kinase.

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WW and SH3 domains, two different scaffolds to recognize proline‐rich ligands

Cited by 437 publications

References 42 publications

EGR-1 forms a complex with YAP-1 and upregulates Bax expression in irradiated prostate carcinoma cells

EGR-1 forms a complex with YAP-1 and upregulates Bax expression in irradiated prostate carcinoma cells

Y65C Missense Mutation in the WW Domain of the Golabi-Ito-Hall Syndrome Protein PQBP1 Affects Its Binding Activity and Deregulates Pre-mRNA Splicing

Transactivation of Abl by the Crk II adapter protein requires a PNAY sequence in the Crk C-terminal SH3 domain

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