The HSP90-SYK complex regulates survival of BL cells. The HSP90 inhibitor AT13387 interferes with BL B-cell survival and signaling activity. By SILAC-based phosphoproteomic analysis, Walter et al show dramatic reduction (upper left panel) of phosphorylation of BCR-associated molecules, including LYN, SYK, and BTK, which results in reduction of BL cell viability (bottom left panel). Interestingly, HSP90 is identified as a binding partner for SYK kinase (upper right panel), and such interaction is mediated by phosphorylated tyrosine Y197 on HSP90. Apoptotic effects mediated by HSP90-SYK inhibition largely rely on HSP90-mediated destabilization of SYK kinase, as a constitutively active SYK-isoform (bottom right panel) can rescue BL cells from drug-induced apoptosis. C_H, constant region of the heavy chain; C_L, constant region of the light chain; DMSO, dimethyl sulfoxide; Igα, immunoglobulin α; Igβ, immunoglobulin β; IgG, immunoglobulin G; IP, immunoprecipitation; ns, not significant; P, phosphorylation ; V_H, variable region of the heavy chain; V_L, variable region of the light chain. See Figures 2, 4, and 6 in the article by Walter et al that begins on page 598.