Three modes of 14-3-3 binding to GPIb and the toggle switch hypothesis on VWF binding to GPIb-IX regulation by cAMP signaling. (A) Dimeric 14-3-3 binds to both GPIbα C-terminus and PKA-phosphorylated GPIbβ. This binding mode is associated with a low GPIb-IX affinity for VWF. (B) Dimeric 14-3-3 binds to the GPIbα C-terminus and to an internal site in GPIbα, which overlaps with the filamin binding site; this mode is associated with GPIbβ dephosphorylation and high GPIb-IX affinity for VWF. In this interaction mode, 14-3-3 may compete with or modulate GPIb-IX interaction with filamin A. (C) 14-3-3 dimer binds to GPIbα C-terminus, potentially linking GPIb-IX to another intracellular protein.