Model for Tks5 activation and cell–cell fusion mediated by circumferential podosomes/invadopodia. Tks5 is activated by binding to PtdIns(3,4)P₂ or PtdIns(3,4,5)P₃ through its PX domain as well as by phosphorylation by Src, resulting in the adoption of an “open” conformation amenable to interaction with other proteins. Activated Tks5 then promotes the formation of circumferential podosomes/invadopodia. Membranes thus are brought into close proximity [A], and the two outer leaflets (blue) fuse to form a hemifusion stalk [B]. The hemifusion stalk then expands to form a hemifusion diaphragm, with the inner leaflets (red) being in contact [C]. Rupture of the hemifusion diaphragm results in formation of the fusion pore [D]. Production of PtdIns(3,4)P₂ or PtdIns(3,4,5)P₃ (green) may trigger the latter steps by inducing the Tks5-dependent formation of circumferential podosomes/invadopodia.