WISp39 and Hsp90: actin' together in cell migration

Cell motility is an actin dependent process requiring the formation and extension of lamellipodia or filopodia, and is absolutely essential for many cellular processes, especially for morphogenesis during development. During lamellipodial extension, actin dynamics involve switching between branch formation at the leading edge and proximal severing of existing actin filaments [1]. Actin branch formation by the Arp2/3 complex changes cell shape and produces protrusions. In addition, the actin depolymerizing factor Cofilin maintains actin turnover by severing and depolymerizing actin filaments [2]. However, a molecular understanding of how actin treadmilling, driven by Arp2/3 dependent branching at the leading edge, is balanced with Cofilin-dependent severing toward the cell interior has remained incomplete. What is known is that Arp2/3 dependent actin assembly and Cofilin dependent disassembly are coordinately regulated at the leading edge by Coronin 1B, which binds the Arp2/3 complex in a phosphorylationdependent manner. When dephosphorylated, Coronin 1B inhibits the binding of the Arp2/3 complex to actin, but phosphorylation by protein kinase C at Ser2 reduces its association with the Arp2/3 complex, enabling actin branch formation [3]. Thus, the regulation of phosphorylated Coronin 1B is essential to control Arp2/3 complex activity and ultimately the rate of actin nucleation and branching at the leading edge. Cofilin is also regulated by phosphorylation but, in contrast to Coronin 1B, it is inactivated by phosphorylation, and becomes active through Slingshot phosphatase (SSH) dephosphorylation [2]. The first indication that Coronin 1B regulates Cofilin came from work showing that Coronin 1B interacts with and is dephosphorylated by SSH, and that this interaction then promotes the dephosphorylation and activation of Cofilin [3]. One crucial missing piece of the puzzle is how the Coronin 1B and SSH interaction is regulated to control dephosphorylation of Cofilin, thus sustaining leading edge actin dynamics. Our recent study has revealed two new important players in cellular motility. We have found that WISp39 (Waf1 Cip1 stabilizing protein 39), an Hsp90 binding Editorial