User:Felix Peix/Sandbox 968
From Proteopedia
Human Serine/Threonine/Tyrosine – interacting protein (STYX) is a catalytically inactive phosphatase, which belongs to the family of dual-specificity phosphatases (DUSPs). It is catalytically inactive due to one mutation of a cysteine residue, which is essential for catalytic activity in normal phosphatases. Through regulation of ERK signalling STYX influences an array of ERK-dependent processes.
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Description
As aforementioned, is classified into the family of dual-specificity phosphatases. This family contains apart from STYX several catalytically active members. In general, they are able to dephosphorylate serine, threonine and tyrosine residues. DUSPs in turn belong to the class I of the protein tyrosine phosphatases (PTPs) group. These class I protein tyrosine phosphatases all have in common that their catalytic mechanism is mainly dependent on a cysteine residue in the active site. This cysteine residue is part of a motif, which is conserved throughout all members of this phosphatase group. In STYX the catalytic cysteine at position 120 is mutated to glycine, which renders this phosphatase unable to catalyze the dephosphorylation of its substrates due to a single mutation (C120G). Hence, it is called a pseudophosphatase.
In general, phosphatases are designated as pseudophosphatases, when they contain at least one mutation in conserved phosphatase domains which are thought to be essential for the catalysis. This definition is of theoretical nature: the catalytic inactivity of most pseudophosphatases is just predicted based on the sequence since the majority of this class of proteins is widely unexplored. Data on substrates and/or possible residual catalytic activity lack for the majority of these proteins. Nevertheless, recent data indicates several roles for pseudophosphatases in physiology and disease (Reiterer, Eyers et al.).
For the cellular functions of STYX, Reiterer, Fey et al. could show that it is predominantly localized in the nucleus where it interacts with the MAP kinases ERK1/2. There STYX competes with the catalytically active dual-specificity phosphatase 4 (DUSP4) for ERK binding. When bound to phosphorylated or dephosphorylated ERK it functions as a nuclear anchor for ERK1/2. Thereby ERK signalling is regulated by STYX. Depletion of STYX was shown to have several strong effects on ERK signalling including an increase in ERK activity and a fragmentation of the Golgi apparatus, which is mediated by the altered ERK activity. The Golgi fragmentation in turn affects Golgi polarization which is an important process in migrating cells. The ability to migrate is one of the major abilities of metastasizing cancer cells. Therefore a link to a role in metastasis is conceivable and some evidence suggests a potential role of STYX in metastasis as described in the paragraph on the biological relevance of STYX.
Structure
STYX is a monomer, that consists of 223 amino acids and has a molecular weight of 25,492 Da. Three ligands, more precisely two sulfate ions and one glycerol are complexed with STYX. As it belongs to the PTPs, it possesses a protein-tyrosine phosphatase domain with substrate binding motifs. These motifs permit the protein to bind its substrates and are found in all PTPs.
The protein-tyrosine phosphatase domain of STYX includes the residues 96 to 167 comprising 4 and a β-sheet containing the active site motif (LVHGNAGISRS) between position 117-127. At position 120 the normally existing catalytic cysteine is replaced by a glycine, which abrogates the catalytic activity. Back mutation of the glycine to cysteine restore catalytic activity, because in this case cysteine undertakes a nucleophilic attack on the phosphoryl group of the substrate. This catalysis mechanism (nucleophilic attack of cysteine) is the same in all “normal” (catallytically active) phosphatases in the class I PTP group. Studies also show that catalytically inactive cysteine mutants bind phosphoproteins in a manner identical to normal phosphatases, indicating that the substrate binding and targeting residues are outside the active site.
Biological Relevance
STYX is an important regulator of ERK signalling in the nucleus. ERK1/2 in turn play roles in several important cellular processes including proliferation and differentiation. ERK signalling is also involved in disease: it is known that in many types of cancer ERK signalling is hyperactivated, which leads to hyperproliferation. Furthermore ERK seems to be involved in epithelial-mesenchymal transition (Shin, Dimitri et al.) (EMT) which is a transcriptional program, which cancer cells have to undergo to break out from the primary tumor into a blood vessel. Since STYX regulates ERK activity, STYX could play a role in this disease.
Indeed, several pieces of evidence suggest a role for STYX in cancer. First of all, it could be shown that STYX depletion causes Golgi fragmentation. When the Golgi apparatus is fragmented, the polarization of the cell before starting migration doesn't work properly anymore and as a result the migrating ability is impaired. The migrating ability of cancer cells is crucial in the process of metastasis, therefore a role of STYX in cancer metastasis is conceivable. This theory is also supported by data from STYX gene expression studies in breast carcinoma. Three independent studies in breast carcinoma all indicate that STYX expression is enhanced.
All in all a lot of research has to be conducted on this special enzyme to further elucidate its role in the prominent ERK signalling pathway.
