The role of Syk protein tyrosine kinase in B cell development and function

Schweighoffer, Edina (2002). The role of Syk protein tyrosine kinase in B cell development and function. PhD thesis The Open University.



Signals reaching B cells through the B cell antigen receptor (BCR) expressed on the cell-surface can affect both the development, differentiation and activation status of B cells. One of the early mediators of signalling through the BCR is the protein tyrosine kinase (PTK) Syk. The exact mechanisms how Syk gets recruited to the BCR, how it becomes activated and what the downstream targets are in different responses still need to be clarified.

Gene targeted homozygous mutant (Syk°) mice stress the importance of Syk in BCR signalling. B cell development is severely affected in these mice: very few cells reach the immature stage, and even these are prevented from further maturation, pointing to at least two steps in B cell differentiation where Syk is implicated.

To further explore the relative contribution of Syk and two other tyrosine kinases, Lyn and ZAP-70, to the early steps of B cell development, I conducted genetic experiments, generating double knockout (Syk°Lyn° and Syk°ZAP-70°) animals.

Analyses of these mice revealed a survival role for Syk and Lyn, a survival and differentiation role for Syk and ZAP-70. This latter was surprising, since ZAP-70 has not been assumed to function in B cell lineage cells. Results presented here demonstrate that ZAP-70 is indeed expressed and functional within B lineage cells, and can replace Syk in some, but not all aspects of pre/BCR signalling.

Importantly, pre-BCR signalling leading to differentiation (as defined by changes in surface protein expression), proliferation and allelic exclusion cannot proceed without the involvement of at least one of the Syk/ZAP-70 family protein kinases.

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