9/3/2023 0 Comments Duolink image tool![]() The findings summarized above led to a model in which membrane-inserted FGF2 oligomers serve as intermediates in FGF2 membrane translocation. Recently, key steps of FGF2 membrane translocation were reconstituted using giant unilamellar vesicles with all components being purified to homogeneity 22. These findings are in line with the observation that FGF2 retains a fully folded state during membrane translocation to the cell surface 24, 25. In addition, two cysteine residues (C77 and C95) of FGF2 play a critical role in PI(4,5)P 2-dependent formation of membrane-inserted FGF2 oligomers 23 that represent dynamic intermediates of FGF2 membrane translocation 5, 7. Consistently, residues in FGF2 that mediate interactions with PI(4,5)P 2 and heparan sulfates as well as the residue that is phosphorylated by Tec kinase have been identified and shown to be critical for efficient secretion of FGF2. Unconventional secretion of FGF2 depends on interactions with the α1 subunit of the Na,K-ATPase 15, Tec kinase 16, 17, and the phosphoinositide PI(4,5)P 2 17, 18, 19 at the inner plasma membrane leaflet as well as heparan sulfate chains of proteoglycans at the outer leaflet 20, 21. This process has recently been visualized in real time in living cells employing single-molecule TIRF microscopy 12. Based upon biochemical reconstitution experiments and bulk measurements of FGF2 secretion from cells, unconventional secretion of FGF2 was found to be mediated by direct translocation of FGF2 across the plasma membrane 12, 13, 14. Following secretion from tumor cells and their cellular microenvironment, FGF2 exerts its biological functions through both autocrine and paracrine signaling mediated by the formation of ternary complexes with FGF high-affinity receptors and heparan sulfates on cell surfaces.ĭespite the biological functions FGF2 exerts in the extracellular space, it lacks a signal peptide required for transport along the classical, ER/Golgi-dependent secretory pathway 5, 6, 10, 11. A typical example is Fibroblast Growth Factor 2 (FGF2) 7, a cell survival factor involved in tumor-induced angiogenesis 8, 9. However, additional mechanisms of protein secretion exist that have collectively been termed ‘unconventional protein secretion’ 5, 6. In eukaryotic cells, the ER/Golgi-dependent secretory pathway represents the major mechanism of protein transport into the extracellular space 1, 2, 3, 4.
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