I am not surprised since there is increasing evidence that under certain conditions ADAMs may be able to cleave a large set of substrates...also be careful with the so-called specific inhibitors since the also affects mmps....

I think because we used prodomains of the ADAMs, we did not affect MMPs too much. But we also didnt't screen all the MMPs either for inhibition. I think it is an interesting finding and would hope for someone to follow up on this. I think MT4-MMP was affected in the screen. The results are in the JBC paper we have on proADAM9.

It is not clear from your description (ADAM inhibitors affecting soluble MT-MMP levels) that this is a direct (proteolytic processing) rather than indirect (signaling) effect. For instance, ADAMs can shed signaling molecules that, in turn, regulate the expression of MMPs and TIMPs, which could lead to your same observation without direct ADAM-mediated processing of the MT-MMPs. Still, ADAM-mediated MT-MMP shedding is certainly plausible and worth further investigation.

We don't have enough information to tell if the inhibitors are affecting proteolytic processing directly. I agree, that the preliminary info necessitates further investigation.

I hope someone will continue to explore what regulates processing of MTMMPs and ADAM family members as well. Not much yet has been done at the transcriptional level. I think we looked at some mRNA levels with the ADAM inhibitors, but not the MTMMPs.

Could you give me a link to the paper with the MT4-MMP you mentioned.

It is a JBC paper on using the prodomain of ADAM9. See Moss et al.

Dear Marcia,

In which system did you measure your MMP expression (RNA) and secretion, because you cite only arrays.

MMPs are proteolytic enzymes; ADAMs also, and it depends if it is an in vitro system, where you have the mastery to know targets (substrate) of MMP and ADAM , or in vivo (ie in humans, whre arrays are also used), where the measure of enzyme level can be affected by pharmacokineic and eliminattion of the product in the body(as said by Mark).

Also, it can be difficult to put directly in parallel a transcriptional level measured by arrays , and the soluble level of the protein after because of post-transcriptional regulations.

Regards

Didier

Didier, all we could sY with our paper was that the levels were lower after treatment with an inhibtor in cells We did not study this further. The work you recommend doing is absolutely necessary to establish if there is inhibion of shedding.

Oh ! I understand.

Yes it would be interesting to be completed to precise the exact step affected.

Regards

Didier