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This very interesting report by Parisiadou et al. shows that LRRK2-mediated phosphorylation of ERM proteins modifies the number of p-ERM-positive and F-actin-enriched filopodia. The authors recognize that, at the subcellular level, where and when LRRK2 modifies the phosphorylation state of ERM proteins remains elusive. Because they are only able to detect LRRK2 protein in the cellular soma, they hypothesize that phosphorylat...
This very interesting report by Parisiadou et al. shows that LRRK2-mediated phosphorylation of ERM proteins modifies the number of p-ERM-positive and F-actin-enriched filopodia. The authors recognize that, at the subcellular level, where and when LRRK2 modifies the phosphorylation state of ERM proteins remains elusive. Because they are only able to detect LRRK2 protein in the cellular soma, they hypothesize that phosphorylation happens in the cytosol and the resulting pERM is then transported to filopodia.
We have recently demonstrated that membrane-associated LRRK2 protein is recruited to filopodia/microvilli upon the formation of these structures, as well as other structures known to be enriched in ERM proteins (Alegre-Abarrategui et al., 2009; Alegre-Abarrategui and Wade- Martins, 2009). These results were achieved by using a novel genomic reporter cellular model to express a YPet-LRRK2 protein from the genomic locus in combination with immunoelectron microscopy. Based on our results, we believe that ERM protein phosphorylation occurs in filopodia upon the active recruitment of LRRK2, which is consistent with the hypothesis that phosphorylated ERM proteins specifically accumulate in filopodia and not in the cytosol (Nakamura et al., 2000).
Alegre-Abarrategui J, Christian H, Lufino MM, Mutihac R, Venda LL, Ansorge O, Wade-Martins R (2009) LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum Mol Genet 18:4022-4034.
Alegre-Abarrategui J, Wade-Martins R (2009) Parkinson disease, LRRK2 and the endocytic-autophagic pathway. Autophagy 5.
Nakamura N, Oshiro N, Fukata Y, Amano M, Fukata M, Kuroda S, Matsuura Y, Leung T, Lim L, Kaibuchi K (2000) Phosphorylation of ERM proteins at filopodia induced by Cdc42. Genes Cells 5:571-581.