Browsing by Author "Holeiter, Gerlinde"

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Open Access
The role of the deleted in liver cancer protein family in breast epithelial cell transformation
(2009) Holeiter, Gerlinde; Pfizenmaier, Klaus (Prof. Dr.)
Three genes of the human genome encode for a subfamily of Rho GTPase-activating proteins (RhoGAPs) termed "deleted in liver cancer" (DLC) proteins. Rho GTPases participate in a complex set of intracellular signaling pathways including the regulation of cytoskeleton dynamics and cell motility. Since RhoGAPs accelerate the transfer of active GTP-bound Rho proteins to the inactive state, they are able to attenuate signal transduction activities of Rho GTPases. In vitro the DLC proteins show GAP activity towards the Rho proteins RhoA and Cdc42 but not for Rac1. DLC proteins have furthermore been identified as binding partners for tensin proteins and localize to focal adhesions. As the name implicates, loss of DLC protein expression has been first observed in hepatocellular carcinomas. Meanwhile, their down-regulation has also been found in a variety of other human cancers, indicating a possible role for the three DLC family members as tumor suppressors. Studies with overexpressed DLC1-3 suggest that they share common cellular functions. Ectopic expression of DLC1, for example, has been shown to inhibit cell migration, proliferation, anchorage independent growth and even metastasis. However, whether the loss of DLC family members is the cause of aberrant Rho signaling in transformed cells has not been investigated. To elucidate the functions of endogenous DLC proteins we silenced DLC1-3 expression in breast cancer cell lines using a RNA interference (RNAi) approach and compared the cellular alterations. We demonstrate that the loss of each DLC family member leads to a distinct cellular phenotype. For instance, knockdown of DLC1 and DLC3 enhanced cell motility in transwell assays, but had a differential impact on random cell migration and RhoA activity. By contrast, DLC2 down-regulation failed to affect cell locomotion, although it led to an enhanced level of active RhoA. Furthermore, we provide data supporting the involvement of DLC1 in the control of directed cell migration through a Dia1- and not Rho kinase (ROCK)-dependent pathway. In summary, we show that despite their overlapping substrate specificity towards RhoA in vitro, DLC family members have non-redundant cellular functions. We assume that this is most likely due to their multimodular structures, distinct spatial distributions and interaction with different signaling proteins in intact cells.