Modeling of the PAG/Lyn SH2 complexes and Lyn, PAG, STAT3, and Csk interactions in lymphoma cell membranes. (A) Binding models of PAG (red) and Lyn SH2 (blue) and the fitting of Lyn SH2 are shown for both nonphosphorylated and phosphorylated (Y299 and Y317) PAG. The orientation of phosphorylated PAG is different from that of nonphosphorylated PAG. The phosphorylated PAG constitutes a best-fitting model. The N- and C-termini of Lyn SH2 (small arrowheads) are facing the nonphosphorylated PAG structure, and SH2 binding to PAG should be affected when the complete Lyn protein interacts with PAG. In contrast, the N- and C-termini of Lyn SH2 (small arrowheads) are facing away from the contact area with the phosphorylated PAG structure, an orientation that is likely not to be affected when the whole Lyn protein interacts with phosphorylated PAG. (B) The residue per residue contact maps show the residues involved in the contact area for phosphorylated PAG. The Lyn residues involved in contacts are shown in the vertical axis and PAG residues on the horizontal axis. Y299 of phosphorylated PAG is shown to make contacts with Pro 18, Gly 19, Asn 20, Ser 21, Ala 22, Arg 42, and Asp 50 of Lyn SH2. The encircled area of Lyn SH2 (Figure 7A) contains Pro 46, Val 47, and His 48 (in a coiled region between 2 β-sheets) that make contacts with different residues of phosphorylated PAG. (C) According to Cary and Cooper,¹⁶  Csk docks onto PAG (pY317), phosphorylates Lyn pY507, causing the Lyn SH2 to interact with Lyn pY507 and to form an intramolecular loop, resulting in a Lyn kinase of low catalytic activity. (D) In the raft-based “signalosome” of B-NHLs, the acylated Lyn kinase and the transmembrane PAG are both inserted in rafts. Modular interactions through Lyn SH2 and SH3 further stabilize the Lyn/PAG signalosome. The SH2 of Lyn is not interacting with its regulatory, C-terminal pY507 (intramolecular interaction), but instead with a cleft in PAG containing pY299. The Lyn C-terminal pYQQQ could also be recognized by STAT3 SH2, an interaction that further limits the possibility of intramolecular binding to Lyn SH2. PAG is phosphotyrosylated by Lyn at least at Y299 and Y317, and Lyn autophosphorylates at Y396 in the catalytic domain (SH1) and at the regulatory site Y507.