The Dok-3/Grb2 protein signal module attenuates lyn kinase-dependent activation of syk kinase in b cell antigen receptor microclusters

Abstract

Recruitment of the growth factor receptor-bound protein 2 (Grb2) by the plasma membrane-associated adapter protein downstream of kinase 3 (Dok-3) attenuates signals transduced by the B cell antigen receptor (BCR). Here we describe molecular details of Dok-3/Grb2 signal integration and function, showing that the Lyndependent activation of the BCR transducer kinase Syk is attenuated by Dok-3/Grb2 in a site-specific manner. This process is associated with the SH3 domain-dependent translocation of Dok-3/ Grb2 complexes into BCR microsignalosomes and augmented phosphorylation of the inhibitory Lyn targetSH2domain-containing inositol 5' phosphatase. Hence, our findings imply that Dok-3/ Grb2 modulates the balance between activatory and inhibitory Lyn functions with the aim to adjust BCR signaling efficiency. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.