Protein Tyrosine Phospatase PTPRR isoforms in cellular signaling and trafficking.

Contains fulltext : 27024.pdf (publisher's version ) (Open Access)Previous work has revealed the existence of two Protein Tyrosine Phosphatases in mouse, PTPBR7 and PTP-SL, that were in part identical, suggesting that they originated from the same gene, termed Ptprr (1,5,6). In this thesis, I report on the characterization of the various PTPRR isoforms in neuronal cells and demonstrate that the single copy mouse gene Ptprr gives rise to four mRNAs that encode PTPBR7, PTP-SL and two PTPPBS protein variants through the use of distinct promoters, alternative splicing and differential translation initiation starts. In addition, the receptor-type PTPBR7 protein isoform was found to undergo N-terminal proteolytic cleavage at a furin-like convertase consensus site, adding an additional, fifth, member for which the name PTPBR7-65 was coined. Localization studies that focused on the different PTPRR isoforms revealed that PTPBR7 and PTP-SL are both present and co-localize in late endocytic compartments and in the Golgi area. PTPBR7 shows an additional localization at the plasma membrane (1,7), and interestingly on early endosomes as well. The 42 and 37 kDa PTPPBS proteins are genuine cytosolic proteins. Live-imaging studies revealed that PTPBR7 and PTP-SL vesicles are highly motile in both anterograde and retrograde directions. PTP-SL is involved in the ERK-MAP kinase signaling pathway, but interestingly, we also found it to interact with the 4-adaptin subunit of the AP-4 adaptor complex, an important component of the vesicular transport machinery. Taken together, studies described in this thesis point to a possible role for PTP-SL, and other PTPRR family members, in vesicle trafficking between the Golgi-apparatus and endocytic compartments and localized signaling.RU Radboud Universiteit Nijmegen, 24 november 2005Promotor : Wieringa, B. Co-promotores : Fransen, J.A.M., Hendriks, W.J.A.J.176 p