The involvement of Src family kinases including Lyn in various signaling

Further, the enhanced Th2 response in Lyn mice also appears to be contributed to by the lack of Lyn signals through the FcERI in baso phils, With Lyn also being intimately involved in FcERI signaling within mast cells, a potential to regulate mast cell inflammation associated with allergic reactions also exists, Interestingly, while Lyn abt737 B cells can be autoreactive, the immune disease that they cause is strongly linked to the IL 6 dependent inflamma tory environment that they induce, Additionally, hyperactive myeloid cells produce BAFF that activates B cells, but also activates T cells to release IFN, creating an inflammatory loop that exacerbates the autoimmunity of Lyn animals, There is some interesting data suggesting that the sub cellular localization of Lyn is crucial for its normal func tioning, Lyn can be cleaved by caspase 3 and 7 within its N terminal unique region, resulting in removal of the myristoylation and single palmitoylation sites, resulting in the cleaved form localizing exclusively to the cytosolic compartment, while full length Lyn can be found predominately in the plasma membrane as well as the cytosol, The pro duction of this cleaved form of Lyn occurred in B cells in response to induction of apoptosis, such as via BCR ligation and functions as a suppressor of apoptosis, Intriguingly, when this cleaved form of Lyn is ubi quitously over expressed in transgenic mice, STAT3 is activated and NFκB inhibited, and it induces a skin in flammatory syndrome, very similar to that seen in psor iasis.<br><br> Indeed in skin biopsies of Adriamycin ic50 psoriasis sufferers the cleaved form of Lyn could be detected.<br><br> This phenotype was dependent upon the presence of a TNF TNF re ceptor axis, and was ameliorated in Rag1 deficient mice highlighting the involvement of a T cell response in the observed pathogenesis. Consequently, not only is the activity status AG014699 of Lyn important for immune cell func tion, but also its sub cellular localization. Leukaemia Lymphoma and Lyn The level and or activity of tyrosine kinases including members of the Src family kinases are often ele vated in human neoplastic cells and their activity can correlate with disease severity metastatic potential, Recent advances in the development of small mol ecule inhibitors of tyrosine kinases has resulted in great success in treating particular neoplasms and the thera peutic advantages of these reagents is illustrated by the enormous success of Imatinib mesylate and Dasatinib for the treatment of CML, and the recent release of Tykerb and Sutent for the treatment of solid tumours such as breast, lung and renal cancer.<br><br> While in vivo manipulation of Lyn through knockout, inactivation, and hyper activation mouse models have not provided strong evidence for this kinase having a primary role in initiating neoplasia, substantial evidence does exist im plicating it in regulating cancer leukaemia cell biology, These studies are suggestive that Lyn can be utilized in an oncogene addiction role in these neo plastic cells, subsequent to transformation initiation events involving other molecules. Further, it will be use ful to undertake crosses of Lyn and Lynup up mice with other regulators of oncogensis to delineate pathway interactions.