• We then analyzed the methylation and mutation patterns of the identified gene in 101 thyroid tumors and tested its functions in vitro and in vivo to establish the tumor suppressor role in thyroid cancer. (nih.gov)
  • It is now clear that loss of function of Ras GTPase-activating proteins (RasGAPs) is common in tumors, and germline mutations in certain RasGAP genes are responsible for some clinical syndromes. (nih.gov)
  • Mutants of Ras are found in 25-30% of human tumors. (embl.de)
  • A mouse homologue of the Drosophila tumor suppressor l(2)tid gene defines a novel Ras GTPase-activating protein (RasGAP)-binding protein. (embl.de)
  • Pumping the brakes on RAS - negative regulators and death effectors of RAS. (nih.gov)
  • Here, we will examine how these effectors of RAS contribute to tumor suppression, through both RAS-dependent and RAS-independent mechanisms. (nih.gov)
  • 3. Further augmentation of the biochemical advances should be prioritized: one goal herein might be to develop an in vitro system in which RAS successfully functions in the plasma membrane to activate effectors. (nih.gov)
  • Project 1 aimed to determine which effectors are engaged by each of the mutant proteins, solve the structures of mutant RAS proteins complexed with relevant effectors, and identify new opportunities for small-molecule therapeutics. (nih.gov)
  • RAS-coupled MAPK and PI3K pathways play a fundamental role in thyroid tumorigenesis, and classical genetic alterations upregulating these pathways are well characterized. (nih.gov)
  • Suppression of RASSF protein expression can also promote the development of excessive RAS signaling by uncoupling RAS from growth inhibitory pathways. (nih.gov)
  • The Ras family of GTPases is a collection of molecular switches that link receptors on the plasma membrane to signaling pathways that regulate cell proliferation and differentiation. (embl.de)
  • Among 13 negative modulators of the RAS pathway screened, RASAL1, encoding a RAS GTPase-activating protein, was frequently hypermethylated in thyroid cancers, which was coupled to its silencing in thyroid cancer cells. (nih.gov)
  • As it still remains unclear how these phosphorylations can influence the Ras pathway we have analyzed the ability of p60c-Src and Lck to phosphorylate these two Ras regulators and have compared the activity of the phosphorylated and unphosphorylated forms. (embl.de)
  • However, aberrant upregulation of RAS activity often occurs in the absence of activating mutations in the RAS genes due to defects in RAS regulators. (nih.gov)
  • Differential actions of p60c-Src and Lck kinases on the Ras regulators p120-GAP and GDP/GTP exchange factor CDC25Mm. (embl.de)
  • KRAS binds tightly to RAF kinase in vitro , but activates RAF kinase only at the plasma membrane in vivo . (nih.gov)
  • It is known that the human Ras GTPase activating protein (GAP) p120-GAP can be phosphorylated by different members of the Src kinase family and recently phosphorylation of the GDP/GTP exchange factor (GEF) CDC25Mm/GRF1 by proteins of the Src kinase family has been revealed in vivo [Kiyono, M., Kaziro, Y. & Satoh, T. (2000) J. Biol. (embl.de)
  • In addition to its association with Ras, GAP has been shown to bind to several tyrosine-phosphorylated proteins in cells stimulated by growth factors or expressing transforming tyrosine kinase variants. (embl.de)
  • Progress in the characterization of processed full length KRAS4B and its interaction with cellular membranes stands as a highlight of the RAS Initiative to date. (nih.gov)
  • Here we report the cloning and characterization of a novel GAP-binding protein, mTid-1, a DnaJ chaperone protein that represents the murine homolog of the Drosophila tumor suppressor l(2)tid gene. (embl.de)
  • By examining gene expression patterns of negative modulators of RAS signaling, we attempted to identify potential tumor suppressor genes. (nih.gov)
  • Although regulation of RAS is central to their activity, RasGAPs exhibit great diversity in their binding partners and therefore affect signaling by multiple mechanisms that are independent of RAS. (nih.gov)
  • Despite its obvious importance for carcinogenesis, the role of Gln-61 in the GAP-stimulated GTPase activity of Ras has remained a mystery. (embl.de)
  • The phosphorylation of p120-GAP by p60c-Src inhibited its ability to stimulate the Ha-Ras-GTPase activity, whereas phosphorylation by Lck did not display any effect. (embl.de)
  • Our results suggest that phosphorylation by p60c-Src and Lck is a selective process that can modulate the activity of p120-GAP and CDC25Mm towards Ras proteins. (embl.de)
  • The screening approaches are leading the field into uncharted biological territory and appear wel positioned to serve as robust platforms for current and future collaborations and to accelerate the development of RAS-directed therapies. (nih.gov)
  • 1. The burgeoning industry collaborations that involve this RAS initiative should be used to identify lessons learned that guide development of a generalizable framework for how such activities might be extended going forward. (nih.gov)
  • 2. Continuing development of large-scale approaches to both identify and validate new compounds that selectively inhibit wild-type or mutant RAS. (nih.gov)
  • The RASSF family of tumor suppressors are essential to RAS-induced apoptosis and senescence, and constitute a barrier to RAS-mediated transformation. (nih.gov)
  • Thus, it is important to understand the mechanics of RAS-membrane interaction not only to clarify RAS signal transduction, but also to facilitate future drug discovery efforts directed against RAS itself. (nih.gov)
  • Gln-61 is particularly important because virtually all mutations of this residue eliminate sensitivity to GAPs. (embl.de)