Phosphatase Subfamily STYXL1

Phosphatase Classification: Fold CC1: Superfamily CC1: Family DSP: Subfamily STYXL1

STYXL1 (MK-STYX) is a pseudophosphatase (catalytically inactive) conserved in metazoa but lost in ecdysozoa. Two binding partners have been known so far: phosphatase PTPMT1 and a Ras signaling regulator G3BP1.

Evolution

STYXL1 is found in metazoa but lost in ecdysozoa (arthropods and nematodes) [1]. It is usually found in one copy per genome.

Domain

STYXL1 has an N-terminal rhodanese domain and C-terminal phosphatase domain.

Functions

STYXL1 is expressed in most tissues (see GTEx data).

STYXL1 physically and genetically interacts with the mitochondrial phosphatase PTPMT1, and suppresses PTPMT1 catalytic activity. STYXL1 knockdown induces robust chemoresistance to multiple cytotoxic death-inducing agents. Loss of STYXL1 blocks cytochrome c release, a critical and rate-limiting step in apoptosis. knockdown of PTPMT1 resensitizes STYXL1 knockdown cells to chemotherapeutics and restores the ability to release cytochrome c. This suggests that STYXL1 controls apoptosis by negatively regulating PTPMT1 [2, 3].

STYXL1 also interacts with G3BP-1 (Ras-GTPase activating protein SH3 domain binding protein-1), a key component of stress granules. G3BP1 is an RNA-binding protein with endoribonuclease activity that is recruited to 'stress granules' after stress stimuli. Stress granules are large subcellular structures that serve as sites of mRNA sorting, in which untranslated mRNAs accumulate. A mutant active STYXL1, which has been transformed from pseudophosphatase to phosphatase by restoration of HC of the HCx5R motif, has opposite effects to wild-type STYKL1 (inactive). The active mutant STYXL1 induces stress granules and dephosphorylates G3BP-1. [4, 5].

STYXL1 induces neurite outgrowth in PC12 cells, while the active mutant does not [6]. It is a likely regulator of RhoA signaling in these cells.

References

1. Chen MJ, Dixon JE, and Manning G. Genomics and evolution of protein phosphatases. Sci Signal. 2017 Apr 11;10(474). DOI:10.1126/scisignal.aag1796 |
2. Niemi NM, Lanning NJ, Klomp JA, Tait SW, Xu Y, Dykema KJ, Murphy LO, Gaither LA, Xu HE, Furge KA, Green DR, and MacKeigan JP. MK-STYX, a catalytically inactive phosphatase regulating mitochondrially dependent apoptosis. Mol Cell Biol. 2011 Apr;31(7):1357-68. DOI:10.1128/MCB.00788-10 |
3. Niemi NM, Sacoman JL, Westrate LM, Gaither LA, Lanning NJ, Martin KR, and MacKeigan JP. The pseudophosphatase MK-STYX physically and genetically interacts with the mitochondrial phosphatase PTPMT1. PLoS One. 2014;9(4):e93896. DOI:10.1371/journal.pone.0093896 |
4. Hinton SD, Myers MP, Roggero VR, Allison LA, and Tonks NK. The pseudophosphatase MK-STYX interacts with G3BP and decreases stress granule formation. Biochem J. 2010 Apr 14;427(3):349-57. DOI:10.1042/BJ20091383 |
5. Barr JE, Munyikwa MR, Frazier EA, and Hinton SD. The pseudophosphatase MK-STYX inhibits stress granule assembly independently of Ser149 phosphorylation of G3BP-1. FEBS J. 2013 Jan;280(1):273-84. DOI:10.1111/febs.12068 |
6. Flowers BM, Rusnak LE, Wong KE, Banks DA, Munyikwa MR, McFarland AG, and Hinton SD. The pseudophosphatase MK-STYX induces neurite-like outgrowths in PC12 cells. PLoS One. 2014;9(12):e114535. DOI:10.1371/journal.pone.0114535 |