BLNK mediates Syk-dependent Btk activation

Btk is a critical molecule in B cell antigen receptor (BCR)-coupled signali ng, and its activity is regulated by Lyn and Syk. Although the molecular me chanism of Lyn-dependent Btk activation has been investigated, that of Syk- dependent Btk activation has remained unidentified. We have demonstrated th at BLNK mediates Syk-dependent Btk activation. In a reconstitution cell sys tem, coexpression of BLNK allows Syk to phosphorylate Btk on its tyrosine 5 51, leading to the enhancement of Btk activity. This phosphorylation depend s on the interaction of Btk and BLNK by means of the Btk-Src homology 2 dom ain. The existence of such an activation mechanism is supported by the obse rvation that the BCR-induced Btk phosphorylation and activation are signifi cantly reduced in BLNK-deficient B cells as well as in Syk-deficient B cell s. Although previous observations have identified the function of BLNK as t he linker that integrates the action of Btk and Syk into downstream effecte rs such as phospholipase C gamma2, our present study indicates another func tion of BLNK that connects the activity of Syk to that of Btk.