Members of the TGFbeta family of signaling molecules are found ubiquitously in vertebrates and invertebrates and have critical roles in many essential homeostatic, developmental, and biological processes. To date, all of the known signaling pathways activated by TGFbeta stimulate transcriptional responses. In light of the diversity of TGFbeta's downstream cellular responses, this growth inhibitory polypeptide is likely to be essential for other important cellular functions. We have cloned and sequenced a novel component, termed km23, that directly interacts with and is phosphorylated by the TGFbeta receptors. Based upon its homology to related sequences in the database, we propose that TGFbeta mediates a novel signaling pathway which is critical for intracellular transport along microtubules (MT's). Of interest, we found that a critical site in km23 is mutated in 5 out of 9 ovarian tumor sequences. Although alterations in MT dynamics have been shown to play a role in both cancer development and the mechanism of action of specific chemotherapeutic agents, no link has been noted between control of minus-end MT dynamics and a natural growth regulator such as TGFbeta. Moreover, none of the anti-cancer agents appear to specifically regulate minus-end MT functions. Based upon our preliminary data and the studies proposed herein, we will delineate the steps in this novel pathway, and determine if and how it impinges upon the other major known TGFbeta signaling pathways, the Mapks and the Smads. Laser capture microdissection of normal tissue cells and of tissue cells from various stages of progression of ovarian, breast, and colon cancer will be analyzed to determine the stage at which km23 mutations occur. Molecular profiling studies will address the hypothesis that km23 expression and/or activity is altered when TGFbeta receptors or signaling pathways are modified. Ultimately, we will provide evidence that km23 is a novel molecular target for cancer drug discovery.
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