Involvement of km23 Dynein Light Chains in TGF β Signaling

Abstract

CONTENTS INTRODUCTION THE km23/LC7/ROBL DLC FAMILY km23-1 km23-2 A MODEL FOR km23-1 AND km23-2 IN RECRUITMENT OF TGF-B SIGNALING ENDOSOMES FOR INTRACELLULAR TRANSPORT ALONG MTs FUTURE DIRECTIONS ACKNOWLEDGMENTS REFERENCES Abstract We have identified km23-1 and km23-2 as TGF-~ signaling intermediates that are also light chains of the minus-end directed motor protein dynein. The km23fLC7frobI dynein light chains (DLCs) belong to an ancient superfamily of proteins, known as the MgIB superfamily. Our NMR structural studies demonstrate that km23-1 adopts the structure of a stable homodimer, similar to that of the p14fMAPK scaffolding protein (MPl) 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-~ 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-~ 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-~ signaling components, because disruption of the motor complex blocks transcriptional effects of TGF-~ 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-~ 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 G2fM phase of the cell cycle. Our results implicate km23-1 as a novel. TGF ~-related anti-cancer target for the development of diagnostics and therapeutics.