| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1994: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1993: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Research Abstract |
We have reported a porcine gene sky encoding a non-receptor type 72-kDa PTK (p72^<syk>) which has a distinct structural character, that is the presence of the second src homology region 2 (SH2) instead of SH3, from other members of this group of PTK.Our efforts have in large part focused on the relationship between Syk in the context of surface receptor-initiated signal transduction in B cell and platelet because of their abundant localization.
Stimulation of B lymphocytes through their antigen receptor (BCR) result in rapid increases and induces both an increase of phosphatidylinositol and mobilization of cytoplasmic free calcium. The BCR associates with two classes of tyrosine kinase : Src family kinase and Sky kinase. To dissect the functional roles of these two types of kinase in BCR signaling, Syk-deficient cell and Lyn-deficient cell lines were established. Syk-deficient cells abolished the tyrosine phosphorylation phospholipase C (PLC) -gamma, resulting in no inositol, 1,4,5-tris
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phosphate (IP3) generation, as well as calcium moblization upon receptor stimulation. Crosslinking of BCR on Lyn-deficient cells evoked a delayd and slow calcium moblization, despite the normal kinetics of IP3 turnover. These results demonstrated that Syk mediates IP3 generation, whereas Lyn regulates calcium mobization through a process independent of IP3 generation.
Activation of Syk in platelets is not restricted to thrombin stimulation. Platelet activating factor, thromboxane A2, wheat germ agglutinin, and collagen also activate Syk. These findings imply that Syk may be one of the key molecules through which various receptor signaling acts. Tyrosine phosphorylation of p125^<FAK> is followed by Syk activation upon integrin receptor stimulation, suggesting that phosphorylation of p125^<FAK> may be mediated by Syk. Reinforcing this idea, the physical association of Syk family PTKs with Src family PTKs or FAK family protein is observed. Furthermore, stimulation of platelets by thrombin induces the rapid translocation of Syk from the cytosolic fraction to the membrane and cytoskeletal fraction. This recruitment of Syk to membrane and cytoskeletal fraction may contribute to the thrombininduced activation of Syk. Less
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