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?)


Anonymous said...

Clinically, is phosphorylation in this context responsible for osteopenia?

Terry Hamblin said...

No. This is thr adding od a phosphate group as part of the energy supply of the system.

Nick said...

Thank you for yor teaching I look forward to you expanding on the topic. Can you suggest some good foundation reading material that details the life cycle of a CLL cell and explains the different signaling and interactions during it's journies, following birth.


Dr Stephen Phua, MBBS, FFPM said...


I have a patient with CLL who has aberrant expression of CD22. Based on your argument, wouldn't it be a good prognostic factor since CD 22 suppresses BCR through the Sh1 to dysphosphorylase the tyrosine kinase? He is seen by Keating and is put on Rituxan and Pred; he has unmutated IGHV, p53 mutation, 13q del; absolute lymphocytosis of 30K and beta microglobulin of 3K, no b symptoms, 20 cm spleen, slightly enlarged liver with multisites of slight to moderate enlargement of lymph nodes. Could this be a private discussion? Really appreciate your blog; it has blessed me with a rich source of medical, political, sports and most important spiritual inspiration. I thank the Gracious Lord for your wonderful ministry. May He performs a miracle in your thorn in the flesh and get rid of your mutations of mortality.

Terry Hamblin said...

Thank you.

Unfortunately expression of CD22 tends to be associated with other bad prognostic factors like del 11q, del 17p and trisomy 12 which tend to over-rule.

Keen Eye said...

Does ii mean that on its own, the over expression of CD22 is a favourable prognostic factor?

Terry Hamblin said...

No. If anything it is a bad prognostic factor, but it is probably irrelevant in your case.