Concerted regulation of actin polymerization during constitutive secretion by cortactin and PKD2

Constitutive secretion from the trans-Golgi-network (TGN) is facilitated by a concerted regulation of vesicle biogenesis and fission processes. The protein kinase D family (PKD) has been previously described to enhance vesicle fission by modifying the lipid environment. PKD also phosphorylates the actin regulatory protein cortactin at S298 to impair synergistic actin polymerization. We here report additional functions for PKD2 (also known as PRKD2) and cortactin in the regulation of actin polymerization during the fission of transport carriers from the TGN. Phosphorylation of cortactin at S298 impairs the interaction between WIP (also known as WIPF1) and cortactin. WIP stabilizes the autoinhibited conformation of N-WASP (also known as WASL). This leads to an inhibition of synergistic Arp2/3-complex-dependent actin polymerization at the TGN. PKD2 activity at the TGN is controlled by active CDC42-GTP which directly activates N-WASP, inhibits PKD2 and shifts the balance to non5298-phosphorylated cortactin, which can in turn sequester WIP from N-WASP. Consequently, synergistic actin polymerization at the TGN and constitutive secretion are enhanced.