GRB2

Résumé

Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene. The protein encoded by this gene binds receptors such as the epidermal growth factor receptor and contains one SH2 domain and two SH3 domains. Its two SH3 domains direct complex formation with proline-rich regions of other proteins, and its SH2 domain binds tyrosine phosphorylated sequences. This gene is similar to the sem-5 gene of Caenorhabditis elegans, which is involved in the signal transduction pathway. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene. Function and expression Grb2 is widely expressed and is essential for multiple cellular functions. Inhibition of Grb2 function impairs developmental processes in various organisms and blocks transformation and proliferation of various cell types. It is thus not surprising that

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https://en.wikipedia.org/wiki/GRB2

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High Affinity Molecules Disrupting GRB2 Protein Complexes as a Therapeutic Strategy for Chronic Myelogenous Leukaemia

A review. Chronic myelogenous leukemia (CML) is one of the most intensively studied human malignancies. It has been the focus of major efforts to develop potent drugs for several decades, but until recently cure rates remained low. A breakthrough in CML therapy was very likely accomplished with the clin. introduction of STI-571 in 2000/2001. Despite the hope that STI-571 has generated for many CML patients, development of resistance to this drug is already apparent in some cases, esp. if the CML is diagnosed in its later stages. Therefore, novel drugs which can be used alone or in combination with STI-571 are highly desirable. This review briefly summarizes the current understanding and therapy of CML and then discusses in more detail basic lab. research that attempts to target Grb2, an adaptor protein known to directly interact with the Bcr portion of the Bcr-Abl fusion protein. Blocking the binding of Grb2 to the GDP-releasing protein SOS is well known to abrogate the activation of the GTPase Ras, a major driving force of the central mitogenic (MAP kinase) pathway. Addnl. Grb2 effector proteins may also contribute to the proliferation-inhibiting effects obsd. upon uncoupling Grb2 from its downstream signaling system. Since Grb2 is a known signal transducer for several major human oncogenes, this approach may have applications for a wider range of human cancers. [on SciFinder (R)]

2003

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We report evidence for a mechanism for the maintenance of long-range conserved synteny across vertebrate genomes. We found the largest mammal-teleost conserved chromosomal segments to be spanned by highly conserved noncoding elements (HCNEs), their developmental regulatory target genes, and phylogenetically and functionally unrelated "bystander" genes. Bystander genes are not specifically under the control of the regulatory elements that drive the target genes and are expressed in patterns that are different from those of the target genes. Reporter insertions distal to zebrafish developmental regulatory genes pax6.1/2, rx3, id1, and fgf8 and miRNA genes mirn9-1 and mirn9-5 recapitulate the expression patterns of these genes even if located inside or beyond bystander genes, suggesting that the regulatory domain of a developmental regulatory gene can extend into and beyond adjacent transcriptional units. We termed these chromosomal segments genomic regulatory blocks (GRBs). After whole genome duplication in teleosts, GRBs, including HCNEs and target genes, were often maintained in both copies, while bystander genes were typically lost from one GRB, strongly suggesting that evolutionary pressure acts to keep the single-copy GRBs of higher vertebrates intact. We show that loss of bystander genes and other mutational events suffered by duplicated GRBs in teleost genomes permits target gene identification and HCNE/target gene assignment. These findings explain the absence of evolutionary breakpoints from large vertebrate chromosomal segments and will aid in the recognition of position effect mutations within human GRBs. ©2007 by Cold Spring Harbor Laboratory Press.

2007

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