Natural small-molecule control of chromatin remodelers would be another possible avenue of therapeutic intervention. In mammals, PIP2 levels were found to modulate chromatin association of BAF complexes (47), and later in yeast, inositol hexakisphosphate (IP6) and inositol polyphosphate were shown to modulate the activity of the ATP-dependent chromatin remodeling complexes INO80 and SWR1 (23, 121), which as mentioned above are structurally similar to BAF in mammals. PIP2 binds to a single site in the BAF complex near the ATPase domain of Brg (96). However, to date, the function of PIP2 binding has not been clear and could be a biochemical artifact. Because PIP2 is membrane-associated, it would indicate that modulation by PIP2 would have to occur near a membrane such as the nuclear membrane or the more elusive “nuclear matrix,” a poorly characterized nuclear fraction. Activation of cell signaling pathways leads to the movement of BAF into the nuclear matrix fraction (47), but again there has been no functional characterization of the consequences of this localization. The realization of the importance of BAF complexes in cancer gave new impetus to discover and understand pathways modulating the activity of these complexes, particularly the importance of activated PI3K as a cooperating oncogene.
