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ADAM15/PTK6/cMET interplay: Promotors of prostate cancer progression

Hurtz, Melanie 2017. ADAM15/PTK6/cMET interplay: Promotors of prostate cancer progression. PhD Thesis, Cardiff University.
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ADAM15 is a transmembrane metalloproteinase involved in disease progression and aggressiveness in prostate cancer (PCa). ADAM15 is composed of an extracellular domain, a transmembrane region and an intracellular domain, the latter being subject to splicing due to alternative use of exons 19 to 21. The splice variants that will be subject in this study are ADAM15-A, ADAM15-B, ADAM15-C, ADAM15-D and ADAM15-E. Previously, ADAM15 splice variant A and B were reported to associate with the PCa promotor PTK6 and the cMET adaptor protein Grb2. In order to understand the underlying mechanisms for the contribution of ADAM15 to disease progression in PCa, ADAM15 A-E splice variants, overexpressed in LNCaP and PC3 PCa cells, were biochemically and functionally characterized. Overexpression of ADAM15-A in PC3 led to enhanced invasion upon HGF treatment, which could be reverted by cMET inhibitor treatment. In addition, ADAM15-induced invasion was dependent on its proteolytic activity. Moreover, PC3 cells expressing proteolytically active ADAM15 showed more MMP2 activity compared to cells with the proteolytically inactive ADAM15 mutant in cell supernatants. In contrast to the aggressive, androgen independent PC3, androgen dependent LNCaP cells did not show any response to HGF treatment upon ADAM15 A-E overexpression. All ADAM15 splice variants were found in a complex with PTK6, which could be disrupted upon cMET inhibition in PC3. Strikingly, ADAM15 was found in a complex with cMET/Gab1/Grb2/PTK6. cMET inhibition led to complex loss of cMET/Gab1/PTK6, however, Grb2 remained in complex with ADAM15 regardless of treatment. Unlike cMET, PTK6 activity was not needed for formation of the ADAM15 complex. Analysis of the ADAM15 splice profile in prostate cancer patients and comparison with healthy prostate tissue revealed a significant overexpression of all ADAM15 splice variants. In summary, we show for the first time that ADAM15 is found in a complex with cMET/Gab1/Grb2/PTK6, and importantly, that, this complex formation is dependent on the cMET/HGF axis in PC3 PCa cells. Moreover, we found that proteolytically active ADAM15 resulted in enhanced invasion upon HGF treatment in PC3s. Our data suggest an important role for ADAM15 in prostate cancer disease progression.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Last Modified: 16 Apr 2021 15:14

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