I have seen quite a few blog posts being spawned by the appearance of a particularly interesting publication. In a more destructive vein, I will do the opposite: a blog post spawned by the lack of a publication (interesting or otherwise).
Some of us will have noticed the phenomenon from time to time: I high-profile paper describes an exciting new gene/protein/effect, and then – nothing. You wait 6 months – the group should have a follow-up paper by then. You wait a year – the competitors should have started jumping the bandwagon . You wait three years – still no follow-up, no retraction, nothing.
Several possible scenarios come to mind to explain such ‘ephemeral discoveries’. Maybe the grad student has left and the lab has so many hot topics to work on that one got lost on the way. Maybe later work suggested that the initial publications wasn’t so great after all, perhaps not bad enough to warrant a retraction, but nevertheless with some elements of uncertainty that makes everybody think of moving to another project.
With the discovery I have picked up this time, I suspect that a third explanation applies. But more on this later. What I am talking about is an interesting paper by David Lane’s group, published five years ago in JCB. The paper deals with a protein called Scotin (probably named for the authors location in Dundee, Scotland). I read the paper when it appeared and was quite intrigued by the Scotin protein. First, it is a pro-apoptotic protein induced by p53. This alone is not too special, there are plenty of alleged pro-apoptotic p53 targets out there, from Bax to whatnot. Only a small number of these proteins is thought to relevant for p53-induced apoptosis. What sets apart Scotin from most other p53 targets is that it looks like a receptor.
Scotin is a single-pass transmembrane protein of 240 aa, with an N-terminal signal peptide, followed by a cys-rich ectodomain, a transmembrane domain, and finally a proline-rich cytoplasmic domain. Being a bioinformatician with a strong interest in protein functional prediction, I immediately wanted to know if Scotin really is a receptor and if so, what would it bind to and how would it signal apoptosis. It was quite easy to see that Scotin is not alone but rather is the founding member of ‘Scotin-like family’ with ~9 members in the human genome. It took somewhat longer to realize that the ectodomain is distantly related to that of several other mammalian protein families. In addition, there are a few other features that the Scotin family and those other families have in common. Most of them carry in their cytoplasmic domain highly conserved recognition motifs for WW-domain binding – in particular the class of WW domains found in the Nedd4 family of ubiquitin ligases. The transmembrane domain of all Scotin-related families are very hydrophobic – this is not uncommon for single-pass transmembrane receptors – and they contain palmitoylation motifs at their cytoplasmic face.
This is plenty of evidence that there is a scotin family which is related to certain other protein families. This should offer a good chance to predict scotin’s function, were there not one other detail shared by all of the protein families: a suspicious absence of publications. As I have mentioned above, the JCB paper on scotin was more or less a one-time publication. There was one more paper in 2004 by another group, reporting that scotin is induced not only by p53 but also by p73, but that is the end of the line. The other members of the scotin-family are just a bunch of genome ORFs, many of them apparently misassembled. The other, more distantly related protein families are not much better: Several of the proteins have sensible names and their database entry descriptions contain phrases like ‘induced in melanoma’, ‘overexpressed in many cancer types’ or ‘potential NfkB activator’. But if you look for the corresponding publications – nada.
So, is this all part of the big scotin conspiracy? Not very likely. My best guess is that so far, nobody is convinced that scotin or any of the other proteins is particularly exciting. And the publication in the Journal of Cell Biology – well, I guess that for a someone like David Lane, JCB is a place were you send your less interesting stuff. Needless to say that I play in a different league. Why am I mentioning all of this? One of the aims of ‘Suicyte Notes’ is to speculate on what protein or other finding will be making waves in the future. I venture to say that either Scotin itself, or one of the other members of this class of short PPxY receptors will eventually turn out to be very important. For something.