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Involvement of km23 Dynein Light Chains in TGF β Signaling

  • Chapter
Transforming Growth Factor-β in Cancer Therapy, Volume I

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

We have identified km23-1 and km23-2 as TGF-β signaling intermediates that are also light chains of the minus-end directed motor protein dynein. The km23/LC7/robl dynein light chains (DLCs) belong to an ancient superfamily of proteins, known as the MglB superfamily. Our NMR structural studies demonstrate that km23-1 adopts the structure of a stable homodimer, similar to that of the p14/MAPK scaffolding protein (MP1) heterodimer. Furthermore, our results suggest that km23-1/km23-2 may function as motor receptors to recruit Smads2/3 to the dynein motor complex for endosomal transport, prior to Smad nuclear translocation. Thus, TGF-β signaling endosomes may be natural cargo of the dynein complex. Here, we present a model for how km23 family members may function as motor receptors, and describe the evidence that we have accumulated thus far to support such a model. For example, we have demonstrated that the kinase activity of TGF-β receptor RII directly phosphorylates km23-1 on specific serine residues, resulting in attachment of the km23 DLCs to the rest of the multi-subunit dynein complex. This dynein binding function of km23 appears to be required for the endosomal transport of TGF-β signaling components, because disruption of the motor complex blocks transcriptional effects of TGF-β downstream. Alterations in km23-1 found in the ovarian cancer patients appear to modify km23-1 functions in both binding to the dynein motor complex and TGF-β signaling. In addition, forced expression of km23-1 in ovarian cancer cells suppresses their growth in vitro, and tumorgenesis in vivo, by increasing the number of cells in the G2/M phase of the cell cycle. Our results implicate km23-1 as a novel, TGF β-related anti-cancer target for the development of diagnostics and therapeutics.

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Authors and Affiliations

  1. Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA

    Qunyan Jin MD, Guofeng Gao MD & Kathleen M. Mulder PhD

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  1. Qunyan Jin MD
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  2. Guofeng Gao MD
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Jin, Q., Gao, G., Mulder, K.M. (2008). Involvement of km23 Dynein Light Chains in TGF β Signaling. In: Transforming Growth Factor-β in Cancer Therapy, Volume I. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-292-2_11

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  • DOI: https://doi.org/10.1007/978-1-59745-292-2_11

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