Ral-GTPases: good chances for a long-lasting fame

Abstract

Oncogenic constitutively active RAS mutants are found in 30% of all human cancers. In addition to acquisition of point mutations, functional activation of RAS may occur as a part of altered intracellular signal transduction associated with oncogenic transformation. Since RAS appears as a common signal transduction crossroad for various regulatory pathways, there is hardly an aspect of malignant phenotype that was not described as being affected by its activation (reviewed in Malumbres and Barbacid, 2003;and in Campbell and Der, 2004).Pleiotropic oncogenic properties of RAS are materialized through interaction with multiple downstream effector proteins, which, in turn, also have a solid established role in tumorigenesis. RAS-RAF interaction leads to the activation of RAF kinase and subsequent triggering of MEK-ERK cascade. RAS-PI3K interaction stimulates lipid kinase activity of the latter, resulting in the activation of a network of downstream effectors, which include AKT S6 kinase, several isoforms of PKC and RAC-GEFs. Binding of RAS to the proteins known as RAL-GEFs (RAL GDS, RGL1 and 2, RLF) triggers activation of RAS-related subfamily of small GTPases consisting of two homologous proteins, RAL-A and -B. Molecular mechanisms that imply RAL-mediated signaling in tumorigenesis are the least characterized compared to enormous amount of data accumulated on cancer connection of MEK/ERK and PI3K pathways. Nevertheless, recent works unequivocally indicate that contribution of RAL to the pathogenesis of cancer, in general, and to RAS-dependent cancerogenesis, specifically, was probably underestimated. It is, therefore, understandable why a fresh and comprehensive review by Feig (2003) on RAL-dependent signaling was entitled: 'Ral-GTPases: approaching their 15 min of fame'. In light of this, an elegant study by the Moscow (Russia) group led by A. Tatosyan w (Tchevkina et al., 2004), which establishes a unique role of RAL-A in RAS-mediated metastasis, has appeared just in time.In spite of a relatively good general understanding of RAS contribution to oncogenic transformation, the exact pathways involved in RAS-dependent metastasis are not completely elucidated. To address the role of separate branches of RAS downstream signaling in metastasis, Tchevkina et al. used a unique collection of transformed Syrian hamster embryo fibroblast cell lines generated over the years by G.I. Deichman in the Moscow Cancer Research Center. The collection includes both spontaneously and v-SRC-transformed cell lines with varying and well-characterized in vivo metastatic potential. One of these cell lines, v-SRCtransformed HET-SR, being highly metastatic when injected intravenously in syngeneic animals (experimental metastasis assay, EMA), displayed low metastatic potential when grown as a subcutaneous tumor (spontaneous metastasis assay, SMA). Spontaneous metastatic ability is generally considered as more relevant to the clinical disease as well as a more advanced step of tumor progression since prior to the hematogenous spreading, tumor c...

Phospholipase D Couples Survival and Migration Signals in Stress Response of Human Cancer Cells

“…Although little is known about what activates PLD activity in MDA-MB-231 cells, it is of interest that the regulators of PLD1, RalA and Arf6 (8, 29 -31), are both implicated in the regulation of cell migration. RalA was recently reported to stimulate the metastasis of transformed cells (32,33) and was shown previously to activate metalloproteases (34). Other studies also link PLD activity with protease secretion (35)(36)(37).…”

The Tumor Suppressor PP2A Aβ Regulates the RalA GTPase

“…RalA has been implicated in the regulation of exocytosis, transcription, secretion, cell transformation and tumor progression [reviewed in (Feig, 2003;Feinstein, 2005)]. When we overexpressed HA-tagged-RalA and FLAG-tagged Aβ in 293T cells, we found that immune complexes isolated using either HA-or FLAG-specific antibodies contained both RalA and Aβ ( Figure 3E).…”

SV40 small T antigen and PP2A phosphatase in cell transformation

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