Biomedical subjects

Pablo Rodriguez-Viciana

Publications and source records attributed to Pablo Rodriguez-Viciana.

8 recordsLinked to original sources

PubMed2006

mTOR-independent translational control of the extrinsic cell death pathway by RalA.

Oncogenic potential is associated with translational regulation, and the prevailing view is that oncogenes use mTOR-dependent pathways to up-regulate the synthesis of proteins critical for transformation. In this study, we show that RalA, a key mediator of Ras transformation, is also linked to the translational machinery. At least part of this linkage, however, is independent of mTOR and acts through RalBP1 to suppress cdc42-mediated activation of S6 kinase and the translation of the antiapoptotic protein FLIP(S). This action, rather than contributing to transformation, opens a latent tumor-suppressive mechanism that can be activated by tumor necrosis factor-related apoptosis-inducing ligand. These results show that the translational machinery is linked to tumor suppression as well as cell-proliferative pathways and that the reestablishment of cell death pathways by activation of the Ral oncogenic program provides a means for selective therapeutic targeting of Ral-driven malignancies.

ATP-Binding Cassette Transporters↗

PubMed2006

A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity.

Ras family GTPases (RFGs) are known to share many regulatory and effector proteins. How signaling and biological specificity is achieved is poorly understood. Using a proteomics approach, we have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site of Raf proteins bound to other molecules of M-Ras or Ras. Therefore, distinct RFGs, through independent effectors, can regulate different steps in the activation of Raf kinases. Shoc2 function is essential for activation of the MAPK pathway by growth factors. Furthermore, in tumor cells with Ras gene mutations, inhibition of Shoc2 expression inhibits MAPK, but not PI3K activity. We propose that the Shoc2-PP1c holoenzyme provides an attractive therapeutic target for inhibition of the MAPK pathway in cancer.

Blotting, Western↗

PubMed2006

Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.

Cardio-facio-cutaneous (CFC) syndrome is a sporadic developmental disorder involving characteristic craniofacial features, cardiac defects, ectodermal abnormalities, and developmental delay. We demonstrate that heterogeneous de novo missense mutations in three genes within the mitogen-activated protein kinase (MAPK) pathway cause CFC syndrome. The majority of cases (18 out of 23) are caused by mutations in BRAF, a gene frequently mutated in cancer. Of the 11 mutations identified, two result in amino acid substitutions that occur in tumors, but most are unique and suggest previously unknown mechanisms of B-Raf activation. Furthermore, three of five individuals without BRAF mutations had missense mutations in either MEK1 or MEK2, downstream effectors of B-Raf. Our findings highlight the involvement of the MAPK pathway in human development and will provide a molecular diagnosis of CFC syndrome.

Abnormalities, Multiple↗

PubMed2006

Ras ubiquitination: coupling spatial sorting and signal transmission.

H-Ras, N-Ras, and K-Ras proteins have distinct biological properties, despite ubiquitous expression and similar affinities for regulators and effectors. C-terminal hypervariable regions that distinguish H-Ras, N-Ras, and K-Ras proteins direct them to distinct membrane compartments, where they may encounter regulators and effectors at different local concentrations. Jura and coworkers now report that these membrane-targeting domains direct differential ubiquitination of Ras proteins and so provide a molecular mechanism to explain the sorting process and, perhaps, some of the dramatic differences in biological potency among H-Ras, N-Ras, and K-Ras proteins.

Animals↗

PubMed2006

Characterization of interactions between ras family GTPases and their effectors.

Ras family GTPases (RFGs), when in their active GTP-bound state, interact with a wide array of downstream effectors to regulate many biological functions in different cell types. How signal specificity among the closely related family members is achieved is still poorly understood. There is both promiscuity and specificity in the ability of RFGs to interact with and regulate the various effector families, as well as isoforms within those families. RFGs seem to have individual blueprints of effector interactions, and specificity should be considered in the context of the full spectrum of effectors they regulate. The sequencing of the genome has identified a remarkably diverse number of proteins with domains homologous to the Ras-binding domain (RBD) of known Ras effectors and, thus, with the potential to interact with Ras and/or other RFGs. In addition, other proteins without known RBD types are known to behave as RFG effectors, suggesting even more complexity in the number of effector interactions. Determining which of these many candidates are "true" effectors and characterizing their specificity is a critical step to understanding the specific signaling properties and biological functions of the various RFGs.

Animals↗

PubMed2005

RalGDS comes of age.

Ras proteins send signals through multiple effector pathways. The Raf/MEK/MAPK and PI 3' kinase pathways are well-validated Ras effectors in human cancers, but many other candidate pathways could be equally important. RalGDS is such a candidate: in a new paper from Chris Marshall's group, an important role for RalGDS in Ras transformation in vivo has been established for the first time. Mice lacking RalGDS are defective in tumor formation, possibly because of increased apoptosis in Ras-driven tumors. The hunt for a clear role for RalGDS activation in human cancer is on.

Animals↗

PubMed2005

A conditional feedback loop regulates Ras activity through EphA2.

The EphA2 receptor tyrosine kinase is frequently overexpressed in many cancers, including 40% of breast cancers. Here, we show that EphA2 is a direct transcriptional target of the Ras-Raf-MAPK pathway and that ligand-stimulated EphA2 attenuates the growth factor-induced activation of Ras. Thus, a negative feedback loop is created that regulates Ras activity. Interestingly, the expression of EphA2 and ephrin-A1 is mutually exclusive in a panel of 28 breast cancer cell lines. We show that the MAPK pathway inhibits ephrin-A1 expression, and the ligand expression inhibits EphA2 levels contributing to the receptor-ligand reciprocal expression pattern in these cell lines. Our results suggest that an escape from the negative effects of this interaction may be important in the development of cancer.

Animals↗

PubMed2004

Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate.

Ras family GTPases (RFGs) regulate signaling pathways that control multiple biological processes. How signaling specificity among the closely related family members is achieved is poorly understood. We have taken a proteomics approach to signaling by RFGs, and we have analyzed interactions of a panel of RFGs with a comprehensive group of known and potential effectors. We have found remarkable differences in the ability of RFGs to regulate the various isoforms of known effector families. We have also identified several proteins as novel effectors of RFGs with differential binding specificities to the various RFGs. We propose that specificity among RFGs is achieved by the differential regulation of combinations of effector families as well as by the selective regulation of different isoforms within an effector family. An understanding of this new level of complexity in the signaling pathways regulated by RFGs is necessary to understand how they carry out their many cellular functions. It will also likely have critical implications in the treatment of human diseases such as cancer.

GTP Phosphohydrolases↗