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Gray, EJ, Petsalaki, E, James, DA, Bagshaw, RD, Stacey, MM, Rocks, O, Gingras, AC and Pawson, T (2014) Src homology 2 domain containing protein 5 (SH2D5) binds the breakpoint cluster region protein, BCR, and regulates levels of Rac1-GTP. J. Biol. Chem. 289:35397-408
SH2D5 is a mammalian-specific, uncharacterized adaptor-like protein that contains an N-terminal phosphotyrosine-binding domain and a C-terminal Src homology 2 (SH2) domain. We show that SH2D5 is highly enriched in adult mouse brain, particularly in Purkinjie cells in the cerebellum and the cornu ammonis of the hippocampus. Despite harboring two potential phosphotyrosine (Tyr(P)) recognition domains, SH2D5 binds minimally to Tyr(P) ligands, consistent with the absence of a conserved Tyr(P)-binding arginine residue in the SH2 domain. Immunoprecipitation coupled to mass spectrometry (IP-MS) from cultured cells revealed a prominent association of SH2D5 with breakpoint cluster region protein, a RacGAP that is also highly expressed in brain. This interaction occurred between the phosphotyrosine-binding domain of SH2D5 and an NxxF motif located within the N-terminal region of the breakpoint cluster region. siRNA-mediated depletion of SH2D5 in a neuroblastoma cell line, B35, induced a cell rounding phenotype correlated with low levels of activated Rac1-GTP, suggesting that SH2D5 affects Rac1-GTP levels. Taken together, our data provide the first characterization of the SH2D5 signaling protein.
Amino Acid Motifs/genetics; Amino Acid Sequence; Animals; Brain/cytology; Brain/metabolism; Cell Line, Tumor; GTPase-Activating Proteins/genetics; GTPase-Activating Proteins/metabolism; HEK293 Cells; Humans; Immunoblotting; Immunohistochemistry; K562 Cells; Male; Mice, Inbred C57BL; Neuroblastoma/genetics; Neuroblastoma/metabolism; Neuroblastoma/pathology; Neurons/metabolism; Phosphotyrosine/metabolism; Protein Binding; Proto-Oncogene Proteins c-bcr/genetics; Proto-Oncogene Proteins c-bcr/metabolism; RNA Interference; Rats; Shc Signaling Adaptor Proteins/genetics; Shc Signaling Adaptor Proteins/metabolism; rac1 GTP-Binding Protein/genetics; rac1 GTP-Binding Protein/metabolism