The Roles of Pseudophosphatases in Disease

Abstract

The pseudophosphatases, atypical members of the protein tyrosine phosphatase family, have emerged as bona fide signaling regulators within the past two decades. Their roles as regulators have led to a renaissance of the pseudophosphatase and pseudoenyme fields, catapulting interest from a mere curiosity to intriguing and relevant proteins to investigate. Pseudophosphatases make up approximately fourteen percent of the phosphatase family, and are conserved throughout evolution. Pseudophosphatases, along with pseudokinases, are important players in physiology and pathophysiology. These atypical members of the protein tyrosine phosphatase and protein tyrosine kinase superfamily, respectively, are rendered catalytically inactive through mutations within their catalytic active signature motif and/or other important domains required for catalysis. This new interest in the pursuit of the relevant functions of these proteins has resulted in an elucidation of their roles in signaling cascades and diseases. There is a rapid accumulation of knowledge of diseases linked to their dysregulation, such as neuropathies and various cancers. This review analyzes the involvement of pseudophosphatases in diseases, highlighting the function of various role(s) of pseudophosphatases involvement in pathologies, and thus providing a platform to strongly consider them as key therapeutic drug targets.

Pseudophosphatases as Regulators of MAPK Signaling

“…Mutations within the active enzymes that resulted in pseudophosphatases are essential and critical for their current function (Table 1). There are active phosphatases whose non-catalytic activity is critical for regulation of signaling pathway [25,28]. For example, the non-catalytic activity of phosphatase of regenerating liver-3 promotes metastatic growth [28,85].…”

“…The pseudoenzyme superfamily, first revealed through genomics, consists of a prevalent family of pseudophosphatases, which lacks the ability to catalyze removal of phosphorylated residues [17,20,24,25,[28][29][30]. There is an estimated 13.8% of pseudophosphatases within the human phosphatome.…”

“…Their enzymatic inactivity is due to mutations of critical residues important for the formation of the catalytic center [18][19][20]31]; however, many of these pseudoenzymes maintain a three-dimensional fold [17,18,20], allowing them to bind phosphorylated proteins to regulate other cellular processes [17,20,21,25,32]. For example, pseudophosphatases play a role in spermatogenesis, stress response, apoptosis, neuronal differentiation, cell fate, migration, ubiquitylation, demyelination, and transcription [20][21][22]25,28,[32][33][34][35][36]. Within the past decade, pseudophosphatases have emerged as key regulators in signal transduction cascades by serving as competitors, signaling integrators, modulators, and anchors in cellular processes (Figure 1) [20,21,25].…”

“…Moreover, misregulation of pseudoenzymes has been implicated in various diseases such as cancer and neurological disorders [20,21,25,28,37,38]. As an example, myotubularins (MTMs) are the most prevalent of the pseudophosphatases, forming pseudophosphatase:phosphatase heterodimer signaling complexes.…”

“…These heterodimer signaling complexes are required for cellular processes such as differentiation, membrane trafficking, endocytosis, and survival [20,29,[39][40][41]. Moreover, mutations in the pseudophosphatase or phosphatase components, as well as disassociation of the complex can lead to disease [20,28,42,43], such as Type 4B Charcot-Marie-Tooth disease (abnormal nerve myelination) [28,39,44] and axon degeneration [42,44]. In addition, pseudophosphatases have been implicated as regulators in MAPK signaling pathways, the focus of this review.…”