Cell biology of osteoclasts: GTPases, exchange factors and actin dynamics during bone degradation

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Osteoclasts are multinucleated cells specialized in bone degradation. To digest bone, they need to adhere onto its surface, to build a sealing zone by reorganizing their actin-rich podosomes into tight belts and to modify key steps of membrane traffic. Our proposal focuses on FGD6, a Rho guanine exchange factor strongly upregulated during osteolastogenesis. Our preliminary results indicate that FGD6 regulates podosome formation and potentially the localization of endosomes around podosomal belts. To understand FGD6 function, it will be necessary 1) to study its dynamic behavior in real time, 2) to carefully illustrate the phenotype of osteoclasts depleted in endogenous FGD6, 3) to illustrate how the PH and FYVE phosphoinositide binding domains of FGD6 contribute to its function 4) to identify the FGD6 binding partners, in particular the activated RhoGTPase, and 5) to understand how FGD6 activation and/or localization can be affected by Src and PI-3 kinase signaling. The hypothesis that we want to test is that FGD6 controls podosome dynamics via interactions between its PH domains and PI(3,4,5)P3 of the plasma membrane as well as the localization of early endosomes around podosomal belts via interactions between its FYVE domain and PI3-P of early endosomes, processes that might be regulated by Src-dependent phosphorylation. These studies should pave the way for the functional exploration of other RhoGEFs, which like FGD6 are strongly upregulated during osteoclastogenesis.