Disease relevance of GRB7

• Expression of HER2 and the coamplified genes GRB7 and MLN64 in human breast cancer: quantitative real-time reverse transcription-PCR as a diagnostic alternative to immunohistochemistry and fluorescence in situ hybridization [1].
• Parallel analysis of gene copy number changes and expression levels demonstrated that GRB7 and ERBB2 displayed concomitant elevated expression levels and increased copy numbers in 32% of Barrett's carcinomas [2].
• GRB7 is localized in close proximity to the ERBB2 gene within an amplicon previously identified in Barrett's adenocarcinoma (BCA) [2].
• No alterations, neither gene amplification nor overexpression were detected in Barrett's carcinoma associated low grade intraepithelial neoplasia (LGIN), intestinal metaplasia (IM) and squamous epithelium, indicating that alterations of GRB7 and ERBB2 are late events in the carcinogenesis of Barrett's esophagus [2].
• Transcripts from genes that flank ERBB2 including GRB7, a protein linked to metastasis in esophageal cancer, also showed high levels of expression [3].
• Immunohistochemical analysis on ovarian cancer tissue array confirmed that the upregulated GRB7 was significantly correlated with high-grade ovarian cancer (P = 0.001) [4].

High impact information on GRB7

• Grb14, a member of the Grb7 adaptor protein family, possesses a pleckstrin homology (PH) domain, a C-terminal Src homology-2 (SH2) domain, and an intervening stretch of approximately 45 residues known as the BPS region, which is unique to this adaptor family [5].
• Although both Grb7 isoforms share homology with the Mig-10 cell migration gene, the Grb7V isoform lacks 88 base pairs in the C terminus; the resultant frame shift leads to substitution of an SH2 domain with a short hydrophobic sequence [6].
• Analysis of human esophageal tumor tissues and regional lymph nodes with metastases revealed that Grb7V was expressed in 40% of Grb7-positive esophageal carcinomas [6].
• These findings suggest that Grb7 isoforms are involved in cell invasion and metastatic progression of human esophageal carcinomas [6].
• Finally, transfection of an antisense Grb7 RNA expression construct lowered endogenous Grb7 protein levels and suppressed the invasive phenotype exhibited by esophageal carcinoma cells [6].

Chemical compound and disease context of GRB7

• These findings suggest a possible relationship of Grb7 signaling in association with expression of tyrosine kinase receptors in aggressive human esophageal cancer [7].

Biological context of GRB7

• Screening of a human breast epithelial cell cDNA library with the tyrosine-phosphorylated C terminus of the epidermal growth factor receptor identified a novel member of the GRB7 gene family, designated GRB14 [8].
• These findings may be of particular interest because the transition from high grade intraepithelial neoplasia to invasive carcinoma is a crucial step in malignant transformation in Barrett's carcinogenesis and might underline the putative role of GRB7 and ERBB2 in cell migration and tumor invasion [2].
• We evaluated gene amplification and mRNA expression of GRB7 and ERBB2 in Barrett's carcinoma and its associated precursor lesions to assess their possible role in Barrett's malignant transformation [2].
• Notably, targeted knockdown of either GRB7 or STARD3 also leads to decreased cell proliferation and cell-cycle progression, albeit to a lesser extent compared with ERBB2 knockdown [9].
• Analysis of array-based comparative genomic hybridization and expression profiling data indicate that the minimum region of recurrent amplification (i.e., the amplicon "core") at 17q12 includes two other genes, GRB7 and STARD3, which exhibit elevated expression when amplified [9].

Anatomical context of GRB7

• Activating mutations and/or expression levels of tyrosine kinase receptors GRB7, RAS, and BRAF in testicular germ cell tumors [10].
• Identification of Tyr-703 and Tyr-936 as the primary association sites for Grb2 and Grb7 in the c-Kit/stem cell factor receptor [11].
• We now identify Grb7 as a new RNA-binding protein that serves as the molecular adaptor for transmitting Netrin-1 signals, through focal adhesion kinase (FAK), to the translation machinery [12].
• We find that GRB-7 is amplified in concert with HER2 in several breast cancer cell lines and that GRB-7 is overexpressed in both cell lines and breast tumors [13].
• Although there was no amplification of the Grb7 gene in esophageal cancers, Grb7 mRNA was found to be overexpressed in 14 cancers (43.8%) but not in adjacent normal esophageal mucosa [7].

Associations of GRB7 with chemical compounds

• There was a correlation between GRB7 and ERBB2 in BCA at the DNA level (r(s) = 0.76, p < 0.001) and the mRNA level (r(s) = 0.89, p < 0.001) [2].
• In addition, both FAK binding to PI 3-kinase via its autophosphorylated Tyr(397) and integrin-mediated cell adhesion increased Grb7 association with phosphoinositides [14].
• Although these recognition sequences possess an Asn residue at +2 relative to the phosphotyrosine and therefore represent potential Grb2 binding sites, phosphopeptide competition and "pull-down" experiments demonstrated that they interact preferentially with the Grb7 versus the Grb2 SH2 domain [15].
• Grb7 associated with activated PDGF beta-receptors in vivo, and the association was dramatically reduced by substitution of Tyr-716 or Tyr-775 with a phenylalanine residue [16].
• Using tetracycline-regulated expression system, we showed that overexpression of Grb7 enhanced cell migration toward fibronectin, whereas overexpression of its SH2 domain alone inhibited cell migration [17].

Physical interactions of GRB7

• Moreover, the structure suggests the mechanism by which the Grb7 SH2 domain binds selectively to pTyr-1139 (pYVNQ) in Her2, which along with Grb7 is co-amplified in human breast cancers [18].

Enzymatic interactions of GRB7

• We also found that Grb7 could be phosphorylated by FAK, which was dependent on the FAK kinase activity but not the presence of the Src family kinases [19].

Regulatory relationships of GRB7

• Consistent with previous reports, we also observed that the steroidogenic acute regulatory protein-related gene, MLN64, and growth factor receptor bound protein 7 were coexpressed with ERBB2 [20].
• This study reports an adaptor protein Grb7 that transmits the stimulating signals of Netrin-1 to the translational machinery to rapidly regulate mRNA translation [12].
• Upon binding to its capped, target mRNA, Grb7 blocks the recruitment of eIF4E, rendering mRNA untranslatable [12].

Other interactions of GRB7

• GRB7 is tightly linked to ERBB2 and is coamplified and coexpressed with this gene in several cancer types [21].
• This effort identified ErbB4, one of the EGF/heregulin receptors, and Grb7, an adapter protein associated with ErbB4 (ErbB, epidermal growth factor receptor family protein; EGF, epidermal growth factor; Grb, growth factor receptor bound) [22].
• We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936 [11].
• Our results point to the involvement of several ErbB-specific ligands (amphiregulin and neuregulin 1) and enzymes or adaptor molecules (PI3K, Src, Shc and Grb7) in the ErbB pathway dysregulation associated with breast cancer [23].
• Mutation, elevated expression, and correlations between expression levels of KRAS2, GRB7, and KIT are consistent with their involvement in the development of TGCTs [10].

Analytical, diagnostic and therapeutic context of GRB7

• Phosphopeptide competition and site-directed mutagenesis revealed that Tyr-1139 of erbB2 is the major binding site for the Grb7 SH2 domain, indicating an overlap in binding specificity between the Grb7 and Grb2 SH2 domains [24].
• In human breast cancer cell lines, co-immunoprecipitation of Grb7 with both receptors was detected upon heregulin stimulation [15].
• Using semiquantitative RT-PCR, we detected high levels of Grb7 in 88% of stage IV patients vs only 18% in stage I patients [25].
• Sequence analysis identifies a ras-associating (RA)-like domain in the N-termini of band 4.1/JEF domains and in the Grb7/10/14 adapter family [26].
• Molecular cloning of human GRB-7 co-amplified with CAB1 and c-ERBB-2 in primary gastric cancer [27].

References