Monday, July 18, 2011
Understanding cell signaling
My old friend Stan Wickremasinghe has written a beautiful review of signalling in Brit J Haem and I intend to use it as a teaching tool on this blog. This will be a series of blogs because my experience is that I can only really take in about one fact at a time and since this isn't really my field, I shall be learning too.
The B-cell receptor (BCR) is the B-cells gateway to the outside world. It is in fact an antibody molecule, designed to recognize the antigen that the B-cell is programmed to react with. But it does not connect to anything inside the cell. For this it has to interact with the Ig associated molecules CD79a and CD79b.
When the BCR transmembrane immunoglobulin molecule is engaged by antigen the CD79 a and b proteins of the BCR, the Protein Tyrosine Kinase (PTK), Lyn, is activated. Phosphorylation of tyrosine residues within an immune receptor tyrosine-based activation motif (ITAM) sequence in the C-terminal tail of the CD79 molecules results in recruitment of an additional PTK, Syk, resulting in generation of further phosphotyrosine sites. Binding of the SH2-containing protein phosphatase 1 (Shp1) to immune receptor tyrosine-based inhibitor motifs (ITIMs) on transmembrane molecules (including CD22) results in dephosphorylation of phosphotyrosines, providing negative regulation of BCR signalling.
In plain English, in a B-cell, the immunoglobulin molecule on the surface binds to the antigen it was designed for - eg an anti-measles antibody binds to a measles virus. But a CLL cell is probably only rarely designed to fight measles - it looks like the target for CLL cells are proteins released from dying cells in many cases. The immunoglobulin molecule needs an auxiliary molecule to help it signal - this is CD79 (often low in CLL, so is this why it often does not signal very well?)
Activation of CD79 alerts two tyrosine kinases, Lyn and Syk, which are capable of sending messages onward through the cell. Lyn, at least, is thought to act like a rheostat, controling the strength of signal that is sent onwards. It seems to do this by invoking a suppressing signal, binding to the inhibitory protein Shp1 on CD22, which is normally present on B-cells in association with the BCR. (But surface CD22 on CLL cells is either absent or very reduced. It can be detected intracellularly though. Is there more to learn here?)