Lipids modulate SH2 domain–mediated binding to pY-containing signal transducers.
Major finding: Lipids modulate SH2 domain–mediated binding to pY-containing signal transducers.
Mechanism: Lipids bind to variable sites in SH2 domains to control SH2-mediated protein–protein interactions.
Impact: Targeting lipid-binding sites on SH2 domains may abrogate pY-mediated signaling pathways.
The Src homology 2 (SH2) domain is a protein interaction domain (PID) contained within SRC and other intracellular signal-transducing proteins, many of which drive tumorigenesis, which mediates protein–protein interactions via the docking of SH2 domain–containing proteins to phosphotyrosine (pY) residues on other proteins. Membrane lipids have recently been shown to regulate protein–protein interactions mediated by a different PID and to bind to several SH2 domains. To elucidate the role of lipids in SH2 domain–mediated protein–protein interactions and signal transduction, Park, Sheng, Silkov, Jung, and colleagues performed surface plasmon resonance analysis to systematically characterize the binding affinities of 76 of the 121 known SH2 domains for plasma membrane (PM)–mimetic vesicles which recapitulate the lipid profile of cytofacial PM. Sixty-eight out of the 76 SH2 domains analyzed exhibited moderately high to high levels of affinity for PM-mimetic vesicles. Twelve of 18 SH2 domains exhibited high selectivity for phosphoinositides (PtdInsP), which play important roles in cellular signaling, and PtdInsPs were shown to control the recruitment of SH2 domains to the PM. SH2 domains were shown to contain both pY binding pockets and alternate cationic patches, the latter of which were shown to be the primary PtdInsP-binding sites in SH2 domains. Binding of PtdInsP to the SYK family member zeta-chain T-cell receptor (TCR) associated protein kinase 70 kDa (ZAP70), which contains SH2 domains that bind to TCR, was crucial for ZAP70-mediated downstream T-cell signaling. Similarly, nonspecific lipid binding was required for autophosphorylation of the nonreceptor tyrosine kinase PTK6, an intracellular signal transducer which is upregulated in several types of cancer, including breast cancer. Together, these results show that lipids spatiotemporally modulate protein–protein interactions mediated by SH2 domains in intracellular pY-containing signal transducers to control signaling pathways, and that this pathway represents a potential therapeutic target for patients with cancers driven by SH2 domain–containing proteins.
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- ©2016 American Association for Cancer Research.