The Role of Ral GTPases and Their Targets in Human Bladder Cancer

Consisting of two highly similar paralogs exhibiting >80% amino acid identity, the Ral, or Ras-like GTPases, RalA and RalB, have been associated with key phenotypes in both normal and cancer cells. Ras-mediated transformation of human cells depends on the Ral pathway, particularly RalA, while key phenotypes in invasion and metastasis of cancer cells depend on RalB. Some reports suggest contrasting or even antagonistic functions for these two Ral GTPase, for example, where RalB activation mediates cellular migration but may be opposed by RalA activation. Several limitations, however, exist in the literature. First, despite compelling in vitro findings in model systems, no report to date has systematically analyzed the expression, activation, or mutational state of RalA and RalB or their effector proteins in any tumor type. Secondly, despite reports of roles for Ral in transcription, it is unclear whether any of the dichotomous phenotypic roles for RalA or RalB are explained by differences in downstream dependent transcriptional pathways. Finally, though several genes have been reported to be regulated by Ral in cell lines, no report has systematically determined whether Ral-dependent transcriptional targets mediate any key phenotypes in cancer cells. Herein, we address these important questions, focusing on bladder cancer, the fifth most commonly diagnosed cancer in the United States, and most expensive to treat.

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