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. 2020 Mar 26;21(7):2283. doi: 10.3390/ijms21072283

Figure 3.

Figure 3

Cellular localization and functioning of flotillin-1 regulated by S-palmitoylation, sumoylation, and serine phosphorylation: (A). Trafficking from the endoplasmic reticulum to the plasma membrane. Newly synthesized flotillin-1 is S-palmitoylated by unidentified zDHHC (zDHHCx). This acylation determines trafficking of flotillin-1 to the plasma membrane concomitant with IGF-1 receptor (IGF-1R) trafficking. The exit of S-palmitoylated flotillin-1 can also mediate efflux of caveolin-1 from the endoplasmic reticulum protecting the endoplasmic reticulum from stress, which otherwise would inhibit the synthesis of caveolin-1. At the plasma membrane, flotillin-1 forms hetero-oligomers with flotillin-2 and, upon activation of IGF-1R, undergoes depalmitoylation/repalmitoylation required for prolonged receptor signaling. zDHHC5 and protein depalmitoylases—acyl-protein thioesterase-1/2 (APT1/2) or ABHD17 proteins—probably catalyze these reactions. Since the S-palmitoylation of flotillin-1 is required for its plasma membrane localization, depalmitoylation can be linked with its cycling between the plasma membrane and endosomes either alone or with flotillin-2. (B) Regulation of gene expression in metastatic prostate cancer cells: In these cells, non-palmitoylated flotillin-1 in the endoplasmic reticulum undergoes sumoylation at Lys51 and Lys159 with SUMO-2/3. The reaction is catalyzed by the E2 ligase UBC9. Sumoylated flotillin-1 translocates to the nucleus, binds Snail transcription factor, and protects it from proteasomal degradation. This triggers expression of genes related to ETM transition and metastasis. (C) Endothelial barrier regulation: In endothelial cells, flotillin-1 can be phosphorylated at Ser315 by protein kinase C (PKC). The phosphorylated and probably depalmitoylated flotillin-1 localizes to the cytosol. Subsequent dephosphorylation of flotillin-1 by PP2A allows its plasma membrane association, likely correlated with S-palmitoylation catalyzed by zDHHC5. PP2A-dephosphorylated flotillin-1 contributes to endothelial barrier integrity and angiogenesis. PP2A also inhibits the activity of SK1 which catalyzes phosphorylation of sphingosine, a lipid bound by flotillins. P, phosphorylation; S, sumoylation; Sph, sphingosine. N-myristoylation and S-palmitoylation are marked by green and red bars, respectively.