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13 results for “Grb2”
Unveiling metastable ensembles of GRB2 and the relevance of interdomain communication during folding - available data.
<p>The folding process of multidomain proteins is a highly intricate phenomenon involving the assembly of distinct domains into a functional three-dimensional structure. During this process, each domain may fold independently while interacting with other domains to form a functional protein. The folding of multidomain proteins can be influenced by various factors, including the composition and structure of each domain or the presence of disordered linker regions, as well as the surrounding environment. Misfolding of multidomain proteins can lead to the formation of non-functional structures associated with a range of diseases, including cancers and neurodegenerative disorders. Understanding this process is an essential step for many biophysical analyzes, such as stability, interaction, malfunctioning, and rational drug design. One such multidomain protein is the growth factor receptor-bound protein 2 (GRB2), an adaptor protein essential in regulating cell survival. GRB2 consists of one central Src Homology 2 (SH2) domain flanked by two Src Homology 3 (SH3) domains. The SH2 domain interacts with phosphotyrosine regions in other proteins, while the SH3 domains recognize proline-rich regions on protein partners during cell signaling. In this study, we combined computational and experimental techniques to investigate the folding process of GRB2. We sampled the conformational space through computational simulations and mapped the mechanisms involved by calculating free energy profiles, indicating possible intermediate states. From the molecular dynamics and trajectories, we used the Energy Landscape Visualization Method (ELViM), which allowed us to visualize a three-dimensional representation of the overall energy surface. We identified two possible parallel folding routes that cannot be seen in a one-dimensional analysis, with one occurring more frequently during folding. Supporting these results, we used DSC and fluorescence spectroscopy techniques to confirm these intermediate states in vitro. Finally, we analyzed the deletion of domains to compare our model outputs with previously published results, supporting the presence of interdomain modulation. Overall, our study highlights the significance of interdomain communication within the GRB2 protein and its impact on the formation, stability, and structural plasticity, which are crucial for its interaction with other proteins in key signaling pathways.</p> <p> </p>
Stimulation of the catalytic activity of the tyrosine kinase Btk by the adaptor protein Grb2: Part 2
<p>The Tec-family kinase Btk contains a lipid-binding Pleckstrin homology and Tec homology (PH-TH) module connected by a proline-rich linker to a "Src module", an SH3-SH2-kinase unit also found in Src-family kinases and Abl. We showed previously that Btk is activated by PH-TH dimerization, which is triggered on membranes by the phosphatidyl inositol phosphate PIP<sub>3</sub>, or in solution by inositol hexakisphosphate (IP<sub>6</sub>) (Wang <em>et al.</em> 2015, https://doi.org/10.7554/eLife.06074). We now report that the ubiquitous adaptor protein growth-factor-receptor-bound protein 2 (Grb2) binds to and substantially increases the activity of PIP<sub>3</sub>-bound Btk on membranes. Using reconstitution on supported-lipid bilayers, we find that Grb2 can be recruited to membrane-bound Btk through interaction with the proline-rich linker in Btk. This interaction requires intact Grb2, containing both SH3 domains and the SH2 domain, but does not require that the SH2 domain be able to bind phosphorylated tyrosine residues – thus Grb2 bound to Btk is free to interact with scaffold proteins via the SH2 domain. We show that the Grb2-Btk interaction recruits Btk to scaffold-mediated signaling clusters in reconstituted membranes. Our findings indicate that PIP<sub>3</sub>-mediated dimerization of Btk does not fully activate Btk, and that Btk adopts an autoinhibited state at the membrane that is released by Grb2.</p>
Stimulation of the catalytic activity of the tyrosine kinase Btk by the adaptor protein Grb2: Part 3
The Tec-family kinase Btk contains a lipid-binding Pleckstrin homology and Tec homology (PH-TH) module connected by a proline-rich linker to a "Src module", an SH3-SH2-kinase unit also found in Src-family kinases and Abl. We showed previously that Btk is activated by PH-TH dimerization, which is triggered on membranes by the phosphatidyl inositol phosphate PIP<sub>3</sub>, or in solution by inositol hexakisphosphate (IP<sub>6</sub>) (Wang <em>et al.</em> 2015, https://doi.org/10.7554/eLife.06074). We now report that the ubiquitous adaptor protein growth-factor-receptor-bound protein 2 (Grb2) binds to and substantially increases the activity of PIP<sub>3</sub>-bound Btk on membranes. Using reconstitution on supported-lipid bilayers, we find that Grb2 can be recruited to membrane-bound Btk through interaction with the proline-rich linker in Btk. This interaction requires intact Grb2, containing both SH3 domains and the SH2 domain, but does not require that the SH2 domain be able to bind phosphorylated tyrosine residues – thus Grb2 bound to Btk is free to interact with scaffold proteins via the SH2 domain. We show that the Grb2-Btk interaction recruits Btk to scaffold-mediated signaling clusters in reconstituted membranes. Our findings indicate that PIP<sub>3</sub>-mediated dimerization of Btk does not fully activate Btk, and that Btk adopts an autoinhibited state at the membrane that is released by Grb2.
Stimulation of the catalytic activity of the tyrosine kinase Btk by the adaptor protein Grb2: Part 1
The Tec-family kinase Btk contains a lipid-binding Pleckstrin homology and Tec homology (PH-TH) module connected by a proline-rich linker to a "Src module", an SH3-SH2-kinase unit also found in Src-family kinases and Abl. We showed previously that Btk is activated by PH-TH dimerization, which is triggered on membranes by the phosphatidyl inositol phosphate PIP<sub>3</sub>, or in solution by inositol hexakisphosphate (IP<sub>6</sub>) (Wang <em>et al.</em> 2015, https://doi.org/10.7554/eLife.06074). We now report that the ubiquitous adaptor protein growth-factor-receptor-bound protein 2 (Grb2) binds to and substantially increases the activity of PIP<sub>3</sub>-bound Btk on membranes. Using reconstitution on supported-lipid bilayers, we find that Grb2 can be recruited to membrane-bound Btk through interaction with the proline-rich linker in Btk. This interaction requires intact Grb2, containing both SH3 domains and the SH2 domain, but does not require that the SH2 domain be able to bind phosphorylated tyrosine residues – thus Grb2 bound to Btk is free to interact with scaffold proteins via the SH2 domain. We show that the Grb2-Btk interaction recruits Btk to scaffold-mediated signaling clusters in reconstituted membranes. Our findings indicate that PIP<sub>3</sub>-mediated dimerization of Btk does not fully activate Btk, and that Btk adopts an autoinhibited state at the membrane that is released by Grb2.
Stimulation of the catalytic activity of the tyrosine kinase Btk by the adaptor protein Grb2: Part 1
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Stimulation of the catalytic activity of the tyrosine kinase Btk by the adaptor protein Grb2: Part 2
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Stimulation of the catalytic activity of the tyrosine kinase Btk by the adaptor protein Grb2: Part 3
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MiR-376c down-regulation accelerates EGF-dependent migration by targeting GRB2 in the HuCCT1 human intrahepatic cholangiocarcinoma cell line
GEO Series GSE47186. Homo sapiens. 4 samples. Type: Expression profiling by array.
GRB2 promotes malignant behaviors of breast cancer by modulating the global expression and alternative splicing profiles in SK-BR-3 cells through binding mRNA [fRIP-seq]
GEO Series GSE276963. Homo sapiens. 4 samples. Type: Other.
Loss of GRB2 results in nonreceptive endometrium and female infertility.
GEO Series GSE260505. Mus musculus. 8 samples. Type: Expression profiling by high throughput sequencing.
GRB2 promotes malignant behaviors of breast cancer by modulating the global expression and alternative splicing profiles in SK-BR-3 cells through binding mRNA [RNA-seq]
GEO Series GSE276962. Homo sapiens. 6 samples. Type: Expression profiling by high throughput sequencing.
Clinical Trial of BP1001 (Liposomal Grb2 Antisense Oligonucleotide) in Combination With Dasatinib in Patients With Ph + CML Who Have Failed TKI, Ph+ AML, Ph+ MDS
ClinicalTrials.gov study NCT02923986. IPD Sharing: NO. Countries: 1. Publications: 0.
Comparison of E14.5 embryonic kidney transcriptomes (Grb2 ureteric-specific knockout vs wild-type)
GEO Series GSE163040. Mus musculus. 8 samples. Type: Expression profiling by array.
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