Research Project 2:
Deciphering the physiological roles of the lysosomal phosphatidylinositol- 4,5-bisphosphate 4-phosphatases TMEM55A and TMEM55B
Phosphoinositides are a family of low abundant, short lived lipid molecules that play critical roles in the homeostasis of cellular membrane transport processes. They are derived from phosphorylation of phosphatidylinositol (PtdIns) and are found almost exclusively on the cytosolic leaflet of cellular membranes. Interestingly, different organelles and membranes contain distinct sets of accessible phosphatidylinositol phosphates (PtdInsP). PtdIns(4,5)P2 are highly enriched at the plasma membrane but also present in membranes of endosomes, lysosomes and autolysosomes, where they exert important functions in the regulation of a number of essential cellular processes. These include the reformation of lysosomes from autophagosomes, the regulation of lysosomal ion channels and the degradation of receptors after endocytosis. The levels of the different PtdInsP species are tightly regulated both by phosphorylation and dephosphorylation events mediated by specific PtdIns-kinases and -phosphatases, respectively. Very little is known about the only known PtdIns(4,5)P2 modifying enzymes that are capable to act as PtdIns(4,5)P2 4-phosphatases. The major aim of the project is to gain insight into role of these enzymes by analyzing knockout mice to better understand the physiological function of endo-/lysosomal PtdIns(4,5)P2 and its catabolic product after hydrolysis, PtdIns(5)P.
Ungewickell, A., C. Hugge, et al. (2005). “The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases.” Proceedings of the National Academy of Sciences of the United States of America 102(52): 18854-18859.
Alonso, A. and R. Pulido (2016). “The extended human PTPome: A growing tyrosine phosphatase family.” The FEBS Journal 283(8):1404-29.
Billcliff, P. G. and M. Lowe (2014). “Inositol lipid phosphatases in membrane trafficking and human disease.” The Biochemical Journal 461(2): 159-175.