The Src homology 3 (SH3) region is a small protein domain present in a very large group of proteins, including cytoskeletal elements and signaling proteins. It is believed that SH3 domains serve as modules that mediate protein-protein associations and, along with Src homology 2 (SH2) domains, regulate cytoplasmic signaling. The SH3 binding sites of two SH3 binding proteins were localized to a nine- or ten-amino acid stretch very rich in proline residues. Similar SH3 binding motifs exist in the formins, proteins that function in pattern formation in embryonic limbs of the mouse, and one subtype of the muscarinic acetylcholine receptor. Identification of the SH3 binding site provides a basis for understanding the interaction between the SH3 domains and their targets.

A Src homology 3 (SH3) region is a sequence of approximately 50 amino acids found in many nonreceptor tyrosine kinases and other proteins. Deletion of the SH3 region from the protein encoded by the c-abl proto-oncogene activates the protein's transforming capacity, thereby suggesting the participation of the SH3 region in the negative regulation of transformation. A complementary DNA was isolated that encoded a protein, 3BP-1, to which the SH3 region of Abl bound with high specificity and to which SH3 regions from other proteins bound differentially. The sequence of the 3BP-1 protein is similar to that of a COOH-terminal segment of Bcr and to guanosine triphosphatase-activating protein (GAP)-rho, which suggests that it might have GAP activity for Ras-related proteins. The 3BP-1 protein may therefore be a mediator of SH3 function in transformation inhibition and may link tyrosine kinases to Ras-related proteins.

The turnover and processing of the Alzheimer f/A4 amyloid precursor protein (JIAPP) has been studied

The SH3 binding protein, 3BP‐1, was originally cloned as a partial cDNA from an expression library using the Abl SH3 domain as a probe. In addition to an SH3 binding domain, 3BP‐1 displayed homology to a class of GTPase activating proteins (GAPs) active against Rac and Rho proteins. We report here a full length cDNA of 3BP‐1 which extends the homology to GAP proteins previously noted. 3BP‐1 functions in vitro as a GAP with a specificity for Rac‐related G proteins. Microinjection of the 3BP‐1 protein into serum‐starved fibroblasts produces an inhibition of platelet‐derived growth factor (PDGF)‐induced membrane ruffling mediated by Rac. Co‐injection of 3BP‐1 with an activated Rac mutant that is unresponsive to GAPs, counter‐acts this inhibition. 3BP‐1 does not show in vitro activity towards Rho and, in agreement with this finding, microinjection of 3BP‐1 into fibroblasts has no effect on lysophosphatidic acid (LPA)‐induced stress fiber assembly mediated by Rho. Thus 3BP‐1 is a new and specific Rac GAP that can act in cells to counter Rac‐mediated membrane ruffling. How its SH3 binding site interacts with its GAP activity remains to be understood.

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