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GRB2

Growth factor receptor-bound protein 2 (GRB2) is a ubiquitously expressed, non-enzymatic adapter protein consisting of 217 amino acids with a molecular weight of approximately 25 kDa, essential for mediating intracellular signal transduction by linking activated receptor tyrosine kinases (RTKs) to downstream signaling cascades such as the Ras/MAPK and PI3K/AKT pathways.^[1] GRB2 facilitates cellular processes including proliferation, differentiation, survival, and migration by recruiting guanine nucleotide exchange factors like SOS1 to the plasma membrane upon receptor activation.^[2] Its structure features a central Src homology 2 (SH2) domain flanked by two Src homology 3 (SH3) domains, forming a modular "sandwich" configuration that enables specific protein-protein interactions without catalytic activity.^[3] GRB2 was independently cloned in 1992 from human and rat cDNA libraries as GRB2 by Lowenstein et al. and as ASH by Matuoka et al., respectively, during studies on epidermal growth factor receptor (EGFR) signaling.^[3] The gene is located on human chromosome 17q25.1, spans approximately 88 kb, and its canonical transcript contains 6 exons; it encodes a protein highly conserved across species, sharing 58.8% sequence homology with its Caenorhabditis elegans ortholog Sem-5 and identical sequence between human and rat forms.^[3]^[4] This evolutionary conservation underscores GRB2's fundamental role in metazoan signal transduction, initially highlighted by its ability to couple EGFR autophosphorylation to Ras activation via SH2-SH3 domain interactions.^[5] In RTK signaling, the SH2 domain of GRB2 binds phosphotyrosine residues (e.g., pY1068 and pY1173 on EGFR), while the N-terminal SH3 domain interacts with proline-rich motifs in SOS1 to promote GDP-GTP exchange on Ras, thereby initiating the MAPK/ERK cascade for gene expression regulation.^[1] The C-terminal SH3 domain further engages adapters like Gab1, Shc, and dynamin, branching signals to PI3K/AKT for cell survival and cytoskeletal dynamics, as well as modulating autophagy, DNA repair, and necroptosis.^[2] GRB2 also participates in non-RTK pathways, including T-cell receptor signaling and prolactin signaling, and its dimerization state influences pathway fidelity and oncogenic potential.^[1] Dysregulation of GRB2, often through overexpression, is implicated in various cancers such as breast cancer, leukemia, and hepatocellular carcinoma, where it amplifies aberrant RTK/Ras signaling to promote tumor growth and metastasis.^[1] Additionally, GRB2 interacts with viral proteins such as the NS5A protein of hepatitis C virus and the ORF3 protein of hepatitis E virus, contributing to pathogenesis in these infections.^[2]^[6] As a therapeutic target, antisense oligonucleotides that inhibit GRB2 expression, such as liposomal BP1001, are under investigation in clinical trials for advanced solid tumors.^[1]^[7]

Structure

Domains

GRB2 is a modular adapter protein consisting of three principal domains: an N-terminal Src homology 3 (nSH3) domain, a central Src homology 2 (SH2) domain, and a C-terminal Src homology 3 (cSH3) domain, connected by flexible inter-domain linkers that permit independent functioning of each module.^[8] The human GRB2 protein comprises 217 amino acid residues and is encoded by the GRB2 gene located on chromosome 17q25.1.^[9] These domains enable GRB2 to bridge phosphorylated receptor tyrosine kinases with downstream effectors in signaling pathways. The SH2 domain spans residues 60–152 and consists of about 100 amino acids, folding into a compact structure with a central β-sheet flanked by α-helices that positions key residues for ligand recognition.^[10] It binds with high affinity to phosphotyrosine (pTyr) residues on activated receptors, typically exhibiting dissociation constants (K<sub>d</sub>) in the range of 10–100 nM, which facilitates rapid and specific recruitment to signaling complexes.^[11] A conserved FLVRES motif within the βB strand of the SH2 domain is essential for pTyr coordination, where the arginine residue forms a critical salt bridge with the phosphate group, ensuring selectivity for pTyr-containing motifs such as pY-x-N-x, with x denoting variable residues.^[12] The nSH3 domain, encompassing residues 1–58, adopts a characteristic β-barrel fold composed of five antiparallel β-strands arranged in two orthogonal sheets, creating hydrophobic pockets lined by conserved aromatic residues such as tryptophans and tyrosines that accommodate proline rings.^[13] This domain preferentially binds class II proline-rich motifs of the form P-x-x-P-x-R, where the positively charged arginine enhances affinity through electrostatic interactions with acidic residues on the SH3 surface, enabling association with upstream regulators.^[14] The cSH3 domain, located at residues 154–217, shares a similar β-barrel architecture with the nSH3 domain but exhibits subtle sequence differences, including variations in the ligand-binding grooves that confer preference for class I proline-rich motifs in the orientation R-x-P-x-x-P.^[15] These aromatic residues in the binding site stack against the proline side chains, stabilizing polyproline type II helix conformations of the ligands and supporting interactions with diverse effectors.^[16] Flexible inter-domain linkers connect the modular units, with the linker between the nSH3 and SH2 domains spanning residue 59 and the linker between the SH2 and cSH3 domains covering residues 153 (short flexible regions allowing rotational freedom and simultaneous multi-partner engagement without steric hindrance).^[17] This intrinsic flexibility is crucial for the adapter role of GRB2 in dynamic signaling assemblies.^[18]

Overall architecture

GRB2 exhibits a compact modular design consisting of a central SH2 domain flanked by an N-terminal SH3 domain and a C-terminal SH3 domain, arranged in a linear array connected by flexible linkers that enable multi-valent binding to diverse targets.^[19] This architecture positions the SH2 domain (residues 60-152) to recognize phosphotyrosine motifs on activated receptors, while the SH3 domains (residues 1-58 and 154-217) interact with proline-rich sequences in downstream effectors, facilitating signal propagation without enzymatic activity.^[20] The three-dimensional structure of full-length GRB2 has been resolved by X-ray crystallography at 3.1 Å resolution (PDB: 1GRI), revealing the SH3 domains as independent β-sandwich folds with five β-strands forming two anti-parallel sheets, and the SH2 domain as a mixed α-β fold featuring a central β-sheet flanked by α-helices.^[19] In the crystal, GRB2 forms an embedded dimer in the asymmetric unit, with the SH3 domains in van der Waals contact, though solution studies indicate this is not the predominant physiological state.^[20] No full-length NMR structure exists, but domain-specific structures (e.g., PDB: 1GCQ for SH3) confirm the modular independence.^[21] Conformational flexibility is a hallmark of GRB2's architecture, with the linkers (short regions between domains) allowing independent reorientation of the SH3 and SH2 domains to accommodate simultaneous binding to membrane-bound receptors and cytosolic partners. Nuclear magnetic resonance (NMR) studies demonstrate no stable intramolecular interactions, enabling the protein to adopt extended conformations essential for bridging distant binding sites in signaling complexes.^[22] GRB2 displays high evolutionary conservation, with over 90% sequence identity across vertebrate species, reflecting its critical role in conserved signaling pathways.^[1] The core domain scaffolds have remained largely unchanged since the metazoan divergence approximately 600 million years ago, as evidenced by orthologs in invertebrates like Drosophila (Drk) sharing 50-70% identity with human GRB2.^[23] Biophysically, GRB2 exists as a monomer in solution with a molecular weight of approximately 25 kDa, lacking disulfide bonds and exhibiting high solubility consistent with its cytoplasmic localization.^[1] Small-angle X-ray scattering (SAXS) confirms the monomeric state under physiological conditions, with potential for transient dimerization via SH2 domain swapping in specific contexts.^[24]

Biological function

Signal transduction

GRB2 serves as a key adaptor protein in signal transduction, primarily facilitating the relay of signals from activated receptor tyrosine kinases (RTKs) to intracellular effectors. Upon ligand-induced dimerization and autophosphorylation of RTKs, such as the epidermal growth factor receptor (EGFR) at tyrosine 1068, the SH2 domain of GRB2 binds directly to the phosphotyrosine residue, recruiting the GRB2-SOS complex to the plasma membrane. This translocation positions the guanine nucleotide exchange factor Son of Sevenless (SOS) in proximity to its substrate RAS, enabling efficient activation of downstream cascades. In the RAS-MAPK pathway, GRB2's N-terminal and C-terminal SH3 domains bind proline-rich motifs on SOS, stabilizing the complex and promoting GDP-to-GTP exchange on membrane-anchored RAS.^[25] Activated RAS then recruits and stimulates RAF kinase, which phosphorylates and activates MEK1/2, leading to ERK1/2 activation; this cascade drives cellular processes such as proliferation and differentiation. The GRB2-SOS interaction is essential for this pathway, as disruption impairs RAS activation and subsequent MAPK signaling.^[26] Beyond the RAS-MAPK axis, GRB2 contributes to other signaling branches, including the PI3K-AKT pathway through recruitment of GRB2-associated binders (GAB1 and GAB2). GRB2 binds GAB1/2 via its SH3 domains, facilitating GAB1/2 tyrosine phosphorylation and subsequent docking of the PI3K p85 regulatory subunit, which generates PIP3 and activates AKT to promote cell survival. The dynamics of GRB2-mediated signaling are tightly regulated temporally, with recruitment to the plasma membrane occurring rapidly within seconds of RTK activation, followed by dissociation to prevent sustained signaling.^[27] A key negative feedback mechanism involves ERK1/2-mediated phosphorylation of SOS at multiple sites, which disrupts GRB2-SOS binding and attenuates RAS activation, ensuring signal termination. Experimental evidence underscores GRB2's indispensable role in these pathways; GRB2 knockout mice exhibit embryonic lethality around E7.5, characterized by impaired gastrulation and defective endodermal differentiation due to disrupted MAPK signaling.^[28]

Expression patterns

GRB2 exhibits ubiquitous basal expression across all human tissues, with moderate mRNA levels typically ranging from 10 to 50 TPM (transcripts per million) based on GTEx data, and relatively higher expression observed in the brain (e.g., median ~40 TPM in cortex), heart (~35 TPM in left ventricle), placenta (~45 TPM), and whole blood (~60 TPM).^[2]^[29] The transcriptional regulation of GRB2 is primarily constitutive in most cell types, maintaining steady expression levels essential for basal signaling; however, in specific contexts such as neural crest development, it is upregulated by transcription factors like Foxd3, which binds to regulatory elements to enhance GRB2 promoter activity.^[30] The GRB2 promoter lacks prominent growth factor-responsive elements like those for direct EGF induction, though indirect feedback via MAPK pathways can modestly elevate expression (up to 1.5-2 fold) in response to stimuli in proliferative cells.^[26] During mouse embryogenesis, GRB2 mRNA is detectable as early as E3.5 in the blastocyst, becoming essential for primitive endoderm formation and epiblast proliferation by E6.5; expression peaks during organogenesis around E8.5-E10.5 in tissues like heart and neural structures.^[31] Homozygous Grb2 knockout in mice results in embryonic lethality at E6.5-E7.5 due to impaired cell proliferation and failure in extraembryonic tissue development, though conditional knockouts reveal roles in later neural crest-derived structures, including migration defects leading to craniofacial abnormalities.^[32] Post-transcriptional control of GRB2 involves microRNAs that target its 3' untranslated region (3'UTR) for downregulation, particularly in cancer contexts; for instance, miR-329 binds the GRB2 3'UTR to suppress expression in pancreatic cancer cells, reducing proliferation, while miR-1258 similarly targets it in non-small cell lung cancer to inhibit invasion.^[33]^[34] Alternative splicing of GRB2 is rare in humans, with the primary isoform predominant, but a shorter variant, Grb3-3 (lacking part of the SH2 domain due to exon 4 skipping), occurs at low levels and acts as a negative regulator of RAS signaling by competing for binding partners without full functionality.^[26] Quantitatively, GRB2 protein is predominantly cytosolic at concentrations estimated around 0.1-1 μM in mammalian cells based on proteomic surveys, reflecting its role as an abundant adaptor; it exhibits high stability with a half-life of approximately 20-30 hours under normal conditions, and no significant circadian variations in expression have been reported across tissues.^[29]^[8]

Interactions

Binding partners

GRB2 primarily engages its binding partners through its SH2 and SH3 domains, facilitating molecular interactions in cellular signaling without direct enzymatic activity. The SH2 domain recognizes phosphotyrosine (pTyr) residues on activated receptors and adaptors, while the n-terminal (nSH3) and c-terminal (cSH3) domains bind proline-rich motifs such as PxxP sequences. These interactions are typically high-affinity and stoichiometric in a 1:1 ratio for core partners, with dissociation constants (Kd) in the range of 0.1-1 μM for SH2-mediated bindings, as determined by isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) studies.^[35]^[1] Among receptor tyrosine kinases (RTKs), GRB2 binds directly to the epidermal growth factor receptor (EGFR) via its SH2 domain to pTyr1068 and, to a lesser extent, pTyr1086, recruiting GRB2 to the plasma membrane upon ligand stimulation; this interaction has been confirmed by co-immunoprecipitation (co-IP) and fluorescence resonance energy transfer (FRET) assays. Similarly, GRB2 associates with platelet-derived growth factor receptor (PDGFR) at pTyr716 and insulin receptor (InsulinR) substrates like IRS-1 at pTyr895, all mediated by SH2 recognition of pTyr motifs, with yeast two-hybrid screens validating these RTK engagements. These bindings exhibit 1:1 stoichiometry and affinities in the 0.1-1 μM range, underscoring GRB2's role as an adaptor bridging RTKs to downstream effectors.^[1]^[36]^[35]^[37] GRB2 interacts with guanine nucleotide exchange factors (GEFs) such as SOS1 and SOS2 through their proline-rich domains containing PxxP motifs, which engage both nSH3 and cSH3 domains simultaneously for enhanced avidity; structural studies via nuclear magnetic resonance (NMR) and ITC reveal nSH3 binding to sequences like PVPPPVPPRRRP with higher affinity than cSH3. Additionally, GRB2 binds GAB1 and GAB2 via their proline-rich regions (e.g., residues 503-524 in GAB1) primarily through the cSH3 domain, as evidenced by co-IP and crystallographic data, facilitating GEF recruitment without altering intrinsic exchange activity.^[1]^[35]^[38] Other adaptor proteins include Shc1, where GRB2's SH2 domain binds pTyr317 (and secondarily pTyr239/240) on Shc1, forming a stable Shc1-GRB2-SOS ternary complex confirmed by yeast two-hybrid and co-IP experiments. In T-cells, GRB2 binds the linker for activation of T cells (LAT) via SH2 recognition of multiple pTyr sites (e.g., pTyr171, pTyr191, pTyr226), promoting localized signaling clusters as shown by ITC and co-IP. These interactions highlight GRB2's capacity to link phosphorylated adaptors to GEFs.^[1]^[39]^[40] Inhibitory partners include Sprouty proteins (e.g., Sprouty2), which bind GRB2's nSH3 domain via two proline-rich stretches (residues 59-64 and 303-307 containing PxxP-like motifs), sequestering SOS and confirmed by co-IP and binding assays. The ubiquitin ligase Cbl associates indirectly with GRB2 through ubiquitination sites on shared complexes but also directly via GRB2's SH3 domains to Cbl's proline-rich regions, as demonstrated by co-IP in EGFR and T-cell contexts, leading to regulatory turnover.^[41]^[42]^[1] Quantitative analyses from yeast two-hybrid screens and co-IP studies have identified over 20 potential GRB2 partners across cellular contexts, though the core high-affinity interactors are limited to 5-7 key proteins like those described, with no evidence of homo-oligomerization under physiological conditions. These methods emphasize GRB2's promiscuity tempered by domain-specific selectivity.^[1]^[24]

Regulatory mechanisms

GRB2 activity is modulated through post-translational modifications, including phosphorylation, which alters its interactions and signaling efficiency. Phosphorylation of GRB2 on tyrosine 160 by Src family kinases occurs between the SH2 domain and the C-terminal SH3 domain, as demonstrated in PDGF-stimulated fibroblasts and Src-transformed cells, where mutation of this residue abolishes phosphorylation.^[43] This modification disrupts GRB2 dimerization, promoting aberrant Ras activation observed in malignant tissues such as prostate, colon, and breast cancers.^[44] Additionally, feedback mechanisms involve ERK-mediated phosphorylation of SOS, which destabilizes the GRB2-SOS complex and reduces its affinity, thereby limiting Ras activation and signal propagation in response to stimuli like insulin.^[45] JNK signaling similarly contributes to SOS phosphorylation and GRB2 dissociation, providing a checkpoint for MAPK pathway regulation.^[45] Ubiquitination serves as a key regulatory mechanism for GRB2 turnover and signaling termination. Cbl family E3 ligases, including Cbl-b, promote GRB2 ubiquitination leading to its degradation, which attenuates B-cell receptor signaling and supports germinal center formation.^[46] Potential ubiquitination sites include lysines 44 and 56 in the N-terminal SH3 domain and lysine 109 in the SH2 domain, facilitating processes such as endocytosis of receptor complexes.^[47] This modification enhances lysosomal sorting and downregulates RTK signaling, distinct from receptor ubiquitination but interdependent through GRB2-Cbl bridging.^[48] Localization of GRB2 is primarily cytoplasmic, lacking intrinsic lipid modifications such as myristoylation, which confines it to soluble fractions unless recruited to membranes via partners. Prenylation of associated proteins, like farnesylated RAS, anchors the GRB2-SOS-RAS complex at the plasma membrane to enable efficient nucleotide exchange.80252-4.pdf) Nuclear translocation of GRB2 is infrequent but occurs under DNA damage conditions, such as H₂O₂ treatment, where it binds PTEN to facilitate PTEN's nuclear import and maintenance of genomic stability by modulating Rad51 expression.^[49] Allosteric regulation within GRB2 involves interdomain communication that fine-tunes ligand binding and effector recruitment. Binding of phosphotyrosine ligands to the SH2 domain enhances the affinity of the SH3 domains for SOS1 proline-rich motifs, unidirectionally potentiating the N- and C-terminal SH3 interactions through conformational changes in the linker regions.^[38] NMR relaxation studies reveal inherent flexibility in the SH3-SH2 linkers, allowing dynamic adjustments that support multivalent binding while preventing premature activation.^[50] This crosstalk ensures sequential engagement, where SH2 occupancy relieves steric hindrance on the C-SH3 domain, optimizing Ras pathway initiation.^[51] Feedback inhibition further refines GRB2-mediated signaling, with phosphatases like SHP-2 contributing to homeostasis. SHP-2 binding to GRB2-recruited scaffolds, such as FGFR2, inhibits excessive receptor kinase activity and maintains balanced phosphorylation levels, preventing overactivation of downstream cascades.^[52] In parallel, GRB2 directly activates SHP-2 in a phosphorylation-independent manner via monomeric binding, which modulates adaptor availability and indirectly dampens sustained MAPK signaling.^[53]

Clinical significance

Role in diseases

GRB2 plays a significant oncogenic role in various cancers by amplifying signaling pathways such as EGFR-RAS-MAPK, which promote cell proliferation, migration, invasion, and metastasis. In breast cancer, particularly HER2-positive subtypes, GRB2 is frequently overexpressed, linking receptor tyrosine kinases to downstream effectors and enhancing malignant behaviors including tumor growth and apoptosis resistance.^[54] This overexpression correlates with poorer prognosis and has been observed in cell lines and patient tissues, where GRB2 knockdown reduces proliferation and invasion.^[55] Similarly, in colorectal cancer, GRB2 mediates Met receptor signaling to drive epithelial cell progression and tumor advancement, independent of some adaptor proteins like Gab1.^[56] In chronic myelogenous leukemia, GRB2 interacts with Bcr-Abl via its SH2 domain, activating Ras pathways essential for leukemic cell survival.^[57] Dysregulation of GRB2 contributes to neurological pathologies, notably Alzheimer's disease, through interactions with amyloid precursor protein (APP) and related trafficking mechanisms. GRB2 binds to the intracellular domain of APP (AICD), altering its endosomal trafficking and increasing sequestration in late endosomes, which may exacerbate amyloid-beta accumulation and cytoskeletal instability in neurons.^[58] Elevated GRB2 levels in Alzheimer's models correlate with disrupted cytoskeleton stability and impaired autophagy, potentially linking to synaptic dysfunction and cognitive decline.^[59] Additionally, GRB2's SH3 domain interacts with UVRAG, influencing autophagic flux and APP processing in disease contexts.^[60] In cardiovascular diseases, GRB2 is implicated in pathological hypertrophy and fibrosis. Haploinsufficiency of GRB2 in mouse models attenuates pressure overload-induced cardiac hypertrophy by reducing p38 MAPK and JNK activation, demonstrating its necessity for hypertrophic signaling.^[61] GRB2 facilitates ErbB receptor-mediated pathways that drive cardiomyocyte growth during stress, and its deficiency protects against fibrosis progression.^[62] While direct links to atherosclerosis remain less defined, GRB2's role in vascular smooth muscle cell proliferation via MAPK suggests potential involvement in plaque formation.^[63] Although GRB2 mutations do not cause direct Mendelian disorders, its position in the RAS-MAPK cascade contributes to pathway dysregulation in RASopathies. No primary germline mutations in GRB2 have been firmly linked to developmental syndromes such as Noonan-like phenotypes in humans.

Therapeutic implications

Small molecule inhibitors targeting the SH2 domain of GRB2 have shown promise in preclinical models by blocking phosphotyrosine binding and disrupting downstream signaling in cancer cells. For instance, non-phosphopeptide ligands have been developed with IC50 values of 6.7 μM and 1.3 μM, demonstrating potent inhibition of GRB2 SH2 domain binding and reduced cell motility in vitro.^[64] Similarly, a monocarboxylic acid derivative inhibits the EGFR-GRB2 protein-protein interaction with an IC50 of 8.64 μM, leading to decreased Ras activation in breast cancer cell lines.^[65] Peptide mimetics targeting the SH3 domains, which recognize proline-rich PxxP motifs, have also been designed; dimeric peptides bind with high affinity (Kd ~10^{-8} M) and inhibit GRB2-SOS1 interactions, suppressing proliferation in HER2-positive breast cancer models.^[66]^[67] Indirect strategies aim to disrupt GRB2-mediated signaling by targeting upstream or downstream components. EGFR tyrosine kinase inhibitors such as erlotinib reduce GRB2 recruitment to phosphorylated EGFR in non-small cell lung cancer (NSCLC) cells, thereby attenuating the GRB2-SOS1-Ras axis and enhancing antitumor effects in EGFR-dependent tumors.^[68] Likewise, the SOS1 inhibitor BI-3406 potently blocks the SOS1-KRAS interaction (IC50 ~0.6 nM), indirectly impairing GRB2-recruited SOS1 activity and inhibiting proliferation in KRAS-driven cancers like pancreatic and lung models when combined with MEK inhibitors.^[69] Gene therapy approaches, including RNA interference and editing, have demonstrated efficacy in preclinical settings. Liposomal delivery of GRB2 antisense oligonucleotides (e.g., BP1001) achieves siRNA-mediated knockdown, reducing tumor proliferation by up to 86% in ovarian cancer xenografts and enhancing sensitivity to chemotherapy.^[70] In breast cancer xenografts, GRB2 siRNA knockdown suppresses tumor growth by approximately 50-70% through downregulation of MAPK signaling.^[55] CRISPR-Cas9 editing of GRB2 has been explored in oncogenic models to correct pathway hyperactivation, showing reduced cell invasion in RAS pathway-altered cancers, though applications in RASopathies remain investigational.^[26] GRB2 holds potential as a biomarker for therapeutic response in certain cancers. Elevated MET-GRB2 signaling complexes correlate with aggressive tumor behavior and shorter survival in NSCLC, serving as a predictive marker for poor prognosis and potential responsiveness to MET or RAS pathway inhibitors.^[71] Circulating GRB2-SOS1 complexes may also indicate active RAS signaling, offering a non-invasive diagnostic tool for monitoring pathway activation in leukemia and solid tumors.^[72] As of November 2025, clinical trials targeting GRB2 are advancing, particularly in hematologic malignancies. BP1001, a liposomal GRB2 antisense oligonucleotide, is in a phase II trial (NCT02781883) for acute myeloid leukemia (AML), showing interim response rates of 55-75% (CR/CRi/CRh) when combined with decitabine and venetoclax, with complete remissions observed in refractory patients.^[73]^[74] A separate trial for Philadelphia chromosome-positive leukemias (NCT02923986) was withdrawn without enrollment. Challenges include off-target effects due to GRB2's ubiquitous expression, necessitating combination therapies to mitigate toxicity while enhancing specificity.^[1]

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Deletion mutants of GRB2 demonstrated that pp60c-src phosphorylated GRB2 on a tyrosine residue (residue 160) located between the SH2 domain and carboxyl ...
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Grb2 monomer-dimer equilibrium determines normal versus ...
Jun 24, 2015 · Phosphorylation of Y160 on Grb2 is readily detectable in the malignant forms of human prostate, colon and breast cancers. The self-association/ ...
[41]
https://pubmed.ncbi.nlm.nih.gov/17689925/
[42]
E3 ubiquitin ligase Cbl-b in innate and adaptive immunity - PMC - NIH
It has been shown that Grb2 is degraded in a Cbl-b-dependent fashion and ... K63-linked polyubiquitination, and this process is inhibited by Cbl-b.
[43]
Targeting Grb2 SH3 Domains with Affimer Proteins Provides Novel ...
Aug 22, 2024 · Grb2 (isoform 1) is a 217-amino-acid protein with a predicted molecular mass of 25,206 Daltons. Grb2 consists of an N-terminal SH3 domain (SH3N, ...<|separator|>
[44]
Cbl-dependent Ubiquitination Is Required for Progression of EGF ...
Grb2 can link the multiadaptor protein and ubiquitin ligase Cbl to the EGFR and thereby increase ligand-induced ubiquitination of EGFR (Waterman et al., 2002).
[45]
Grb2 binds to PTEN and regulates its nuclear translocation ... - Nature
Jul 18, 2019 · Grb2 binds to PTEN and regulates its nuclear translocation to maintain the genomic stability in DNA damage response.Missing: life | Show results with:life
[46]
Changes in structural dynamics of the Grb2 adaptor protein upon ...
Grb2 functions in the activation of guanine nucleotide exchange by Ras and proteins of the Rho/Rac families, by binding to the guanine nucleotide exchange ...
[47]
The dynamics of free and phosphopeptide-bound Grb2-SH2 reveals ...
Aug 3, 2020 · We present the first dynamical characterization of Grb2-SH2 domain in the free state and in the presence of phosphopeptide EpYINSQV at multiple timescales.
[48]
Grb2 controls phosphorylation of FGFR2 by inhibiting receptor ...
Feb 18, 2013 · Grb2 inhibits the kinase activity of FGFR2 and the phosphatase activity of Shp2 to maintain homeostasis of receptor phosphorylation in the ...Introduction · Results · Discussion · Materials and methods
[49]
Grb2 binding induces phosphorylation-independent activation of Shp2
Apr 1, 2021 · We find that binding of the adaptor protein Grb2, in its monomeric state, initiates Shp2 activity independent of phosphatase phosphorylation.Missing: PDGFR | Show results with:PDGFR
[50]
GRB2: A dynamic adaptor protein orchestrating cellular signaling in ...
Jul 29, 2024 · While SH2 domains recognize phosphorylated tyrosines, SH3 domains bind proline-rich sequences, enabling GRB2 to engage with various downstream ...
[51]
GRB2 Promotes Malignant Behaviors of Breast Cancer by ... - NIH
May 19, 2025 · GRB2 as a flexible protein and an RBP that is involved in post‐transcriptional regulation in eukaryotes, influencing all stages of mRNA synthesis, modification ...Missing: 193b GRB2b
[52]
Met receptor-induced Grb2 or Shc signals both ... - BMC Cancer
Apr 4, 2014 · These results identify Grb2 and Shc as central signaling effectors of Met-driven progression of intestinal epithelial-derived cancers.
[53]
Grb2 Signaling in Cell Motility and Cancer - PMC - PubMed Central
Here we review the role of Grb2 in cancer and specifically in metastasis-related processes, and summarize briefly the development of anti-cancer ...
[54]
Grb2-mediated alteration in the trafficking of AbetaPP - PubMed
Increase in the concentration of Grb2 confines it in enlarged late endosomes leading to more sequestration of AbetaPP and AICD within these compartments. This ...
[55]
Cellular levels of Grb2 and cytoskeleton stability are correlated in a ...
May 1, 2017 · This study unravels a unique role of Grb2 in protecting the cytoskeletal architecture in AD-like conditions and presents a potential new ...Missing: cytosol | Show results with:cytosol
[56]
Interaction of Grb2 SH3 domain with UVRAG in an Alzheimer's ...
Growth factor receptor-bound protein 2 (Grb2) is an adaptor protein which participates in trafficking pathways alongside its role in signaling.
[57]
The role of the Grb2–p38 MAPK signaling pathway in cardiac ... - NIH
Grb2, in turn, can activate MAPK cascades via an interaction with the Ras guanine nucleotide exchange factor SOS and with other signaling intermediates. We ...
[58]
The role of the Grb2-p38 MAPK signaling pathway in cardiac ...
These results establish that Grb2 action is essential for cardiac hypertrophy and fibrosis in response to pressure overload.
[59]
MAPK Signaling in Cardiovascular Health and Disease - PMC - NIH
To determine the role of Grb2 in the development of pathological cardiac hypertrophy, experiments were performed with Grb2 haplo-insufficient mice [53].
[60]
Predisposing germline mutations in high hyperdiploid acute ...
Germline mutations in RAS pathway genes cause congenital syndromes that predispose to childhood leukemia, thus we explored whether germline mutations in ...
[61]
Germline Variants that Affect Tumor Progression - PMC - NIH
... Ras signaling gene GRB2 is associated with upregulation of Ras target genes. (D) Molecularly, germline variants may alter the function of tumor suppressor ...Germline Variation Shapes... · Figure 1 · Effect Sizes Of Germline...
[62]
Pathogenetics of the RASopathies | Human Molecular Genetics
The RASopathies are a group of medical genetic syndromes that are caused by germ-line mutations in genes that encode components, both positive and negative ...
[63]
Potent inhibition of Grb2 SH2 domain binding by non ... - PubMed
Jan 14, 1999 · Development of Grb2 Src homology 2 (SH2) domain binding inhibitors has important implications for treatment of a variety of diseases, including ...Missing: RG108 | Show results with:RG108<|separator|>
[64]
Synthesis and Structural Characterization of a Monocarboxylic ...
A monocarboxylic inhibitor was designed and synthesized to disrupt the protein-protein interaction (PPI) between GRB2 and phosphotyrosine-containing proteins.Missing: RG108 | Show results with:RG108
[65]
[PDF] 1 Grb2-SH3 ligand inhibits the growth of HER2 cancer cells and has ...
We have designed peptide dimers that specifically bind the two SH3 domains of Grb2 with high affinity (Kd ranging 10. –8. M). 18 . Such a peptide-dimer ...
[66]
Inhibitors of tyrosine kinase proteins induced Ras signaling pathway ...
Peptides and peptidomimetics with very high affinities for either SH3 or SH2 domains of Grb2 were rationally designed from structural data. We describe their ...
[67]
Combined use of anti-ErbB monoclonal antibodies and erlotinib ...
Dec 12, 2012 · Erlotinib treatment was observed to increase EGFR and/or HER2 expression at the plasma membrane level only in NSCLC cell lines sensitive to the ...
[68]
BI-3406, a Potent and Selective SOS1–KRAS Interaction Inhibitor, Is ...
BI-3406, a potent and selective SOS1–KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition.
[69]
Therapeutic efficacy of liposomal Grb2 antisense ... - Oncotarget
Jul 21, 2020 · We also observed a reduction in tumor burden after treatment with L-Grb2 and the anti-VEGF antibody B-20 (86% decrease in tumor weight compared ...
[70]
MET–GRB2 Signaling-Associated Complexes Correlate with ...
Abstract. Purpose: Targeting MET in cancer is hampered by lack of diagnostics that accurately reflect high MET signaling and dependence. We hypothesized.
[71]
The Configuration of GRB2 in Protein Interaction and Signal ... - MDPI
Among these sites, Tyr1068 in EGFR is considered the main binding site for GRB2, while Tyr1086 serves as a secondary binding site, and Tyr1173 is an indirect ...5.1. Role Of Grb2 In... · 5.2. Grb2 Controls Fgf-Fgfr... · 5.5. Role Of Grb2 In The...
[72]
NCT02923986 | Clinical Trial of BP1001 (Liposomal Grb2 Antisense ...
The primary objective of the Phase IIa study is to assess the efficacy of the combination of BP1001 and dasatinib in patients with Ph+ CML, Ph+AML, or high-risk ...
[73]
Interim safety and efficacy of BP1001 in a phase II acute myeloid ...
May 29, 2024 · BP1001, a liposome-incorporated Grb2 antisense oligonucleotide,enhanced cancer cell sensitivity to chemotherapy, such as decitabine (DEC) and ...