Abstract
Hepatoma-derived growth factor (HDGF) is involved in diverse, apparently unrelated processes, such as cell proliferation, apoptosis, DNA-repair, transcriptional control, ribosome biogenesis and cell migration. Most of the interactions of HDGF with diverse molecules has been assigned to the hath region of HDGF. In this study we describe two previously unknown HDGF isoforms, HDGF-B and HDGF-C, generated via alternative splicing with structurally unrelated N-terminal regions of their hath region, which is clearly different from the well described isoform, HDGF-A. In silico modeling revealed striking differences near the PHWP motif, an essential part of the binding site for glycosaminoglycans and DNA/RNA. This observation prompted the hypothesis that these isoforms would have distinct interaction patterns with correspondingly diverse roles on cellular processes. Indeed, we discovered specific associations of HDGF-B and HDGF-C with cytoskeleton elements, such as tubulin and dynein, suggesting previously unknown functions of HDGF in retrograde transport, site directed localization and/or cytoskeleton organization. In contrast, the main isoform HDGF-A does not interact directly with the cytoskeleton, but via RNA with messenger ribonucleoprotein (mRNP) complexes. In summary, the discovery of HDGF splice variants with their discrete binding activities and subcellular distributions opened new avenues for understanding its biological function and importance.
Funding source: European Research Council
Award Identifier / Grant number: FP7/2007-2013
Funding statement: Our sincerest gratitude goes to Ajinkya Kulkarni, Department of Microbial Ecophysiology, University of Bremen for help and advice with the Zeiss ApoTome microscope and Prof. Michael Friedrich as head of the group for enabling the use. We would like to thank Prof. Jörn Bullerdiek, Centre for Human Genetics, University of Bremen, Germany and Prof. Dr. Martin Götte, Department of Gynecology and Obstetrics, University Medical Centre Münster, Germany for providing the cell lines MCF-7 and MDA-MB-231, respectively. The research leading to these results has received – in part – funding from the European Research Council under the European Community’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no. 243195.
Acknowledgments:
Our sincerest gratitude goes to Ajinkya Kulkarni, Department of Microbial Ecophysiology, University of Bremen for help and advice with the Zeiss ApoTome microscope and Prof. Michael Friedrich as head of the group for enabling the use. We would like to thank Prof. Jörn Bullerdiek, Centre for Human Genetics, University of Bremen, Germany and Prof. Dr. Martin Götte, Department of Gynecology and Obstetrics, University Medical Centre Münster, Germany for providing the cell lines MCF-7 and MDA-MB-231, respectively. The research leading to these results has received – in part – funding from the European Research Council under the European Community’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no. 243195.
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