The role of pseudophosphatases as signaling regulators

Abstract

Pseudophosphatases are atypical members of the protein tyrosine phosphatase superfamily. Mutations within their catalytic signature motif render them catalytically inactive. Despite this lack of catalytic function, pseudophosphatases have been implicated in various diseases such as Charcot Marie-Tooth disorder, cancer, metabolic disorder, and obesity. Moreover, they have roles in various signaling networks such as spermatogenesis, apoptosis, stress response, tumorigenesis, and neurite differentiation. This review highlights the roles of pseudophosphatases as essential regulators in signaling cascades, providing insight into the function of these catalytically inactive enzymes.

Pseudophosphatase MK-STYX Alters Histone Deacetylase 6 Cytoplasmic Localization, Decreases Its Phosphorylation, and Increases Detyrosination of Tubulin

“…This report investigated the effects of the pseudophosphatase MK-STYX on HDAC6. Because both HDAC6 and MK-STYX interact with the stress granule nucleator G3BP-1 and they have antagonistic roles in stress granule formation, promotion and inhibition [4,28], it was important to determine whether MK-STYX affects HDAC6 subcellular location and phosphorylation state, as well as the post-translational modification of its substrate, microtubules. We showed that MK-STYX caused a proportion of this cytosolic protein to localize in the nucleus.…”

“…MK-STYX (MAPK (mitogen-activated protein kinase) phosphoserine/threonine/tyrosine-binding protein) is a catalytically inactive member of the protein tyrosine phosphatase (PTP) superfamily, classified as a pseudophosphatase [1,2,3,4]. In MK-STYX, critical histidine and cysteine residues in its PTP active site signature motif (HCX 5 R), which are essential for phosphatase activity, are replaced by phenylalanine and serine residues (FSTQGISR) [1,2,3].…”

“…In MK-STYX, critical histidine and cysteine residues in its PTP active site signature motif (HCX 5 R), which are essential for phosphatase activity, are replaced by phenylalanine and serine residues (FSTQGISR) [1,2,3]. Despite being catalytically inactive, MK-STYX plays an important regulatory role in a number of cellular pathways, including apoptosis, neurite formation, and stress granule assembly [3,4,5,6,7,8,9,10]. Elucidating the molecular mechanisms by which MK-STYX functions as a signaling molecule is a subject of much interest.…”

“…For example, MK-STYX has been shown to promote stress-activated mitochondrial-dependent apoptosis and release of cytochrome c, by sequestering an inhibitor of apoptosis, the mitochondrial phosphatase, PTPM1 (PTP localized to the mitochondrion 1) [8,9]. Similarly, MK-STYX binds G3BP-1 (Ras-GTPase activating protein SH3 domain binding protein-1) [3,4,10], a nucleator of stress granules [11], thereby inhibiting stress granule formation. Stress granules are cytoplasmic aggregates of stalled mRNA [11], which accumulate as an immediate protective response to a stressful environment [12].…”

“…Stress granules are cytoplasmic aggregates of stalled mRNA [11], which accumulate as an immediate protective response to a stressful environment [12]. Interestingly, the inhibitory effects of MK-STYX are independent of the phosphorylation status of G3BP-1 at Ser149, the critical residue that regulates its activity as a stress granule nucleator [4,10,11].…”