The Src homology 2 (SH2) and Src homology 3 (SH3) domain are approximately 50% conserved in various Src family kinase members. Several lines of evidence suggest that in Src these domains are sequence motifs that direct substrate recognition, regulate kinase activity, or control subcellular localization. We sought to investigate the function of the homology domains in human Lyn, and to determine whether the differences between various SH3 domains affect function. To do this, we generated variant forms of Lyn lacking SH2 and SH3 domains, and created chimeras in which the SH3 domains in human c-Src and Lyn were replaced with SH3 domains from other family members. In contrast to similar deletions in Src, forms of Lyn lacking SH2 or SH3 had decreased kinase activity. The SH3 chimeras all had individual characteristics. Insertion of the Blk SH3 domain into Lyn restored kinase activity, while insertion of the Fyn or Src SH3 into Lyn enhanced the kinase activity 2-3-fold. Insertion of the Lyn SH3 into Src also doubled kinase activity. Expression of the Lyn-Src SH3 chimera in mammalian cells induced cell transformation. This study 1) demonstrates that the regulation of Lyn is different than Src, and 2) provides new evidence that despite their homology, there are important functional differences between the SH3 domains of the various Src family members.

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