Pseudophosphatases as Regulators of MAPK Signaling

Int J Mol Sci. 2021 Nov 22;22(22):12595. doi: 10.3390/ijms222212595.


Mitogen-activated protein kinase (MAPK) signaling pathways are highly conserved regulators of eukaryotic cell function. These enzymes regulate many biological processes, including the cell cycle, apoptosis, differentiation, protein biosynthesis, and oncogenesis; therefore, tight control of the activity of MAPK is critical. Kinases and phosphatases are well established as MAPK activators and inhibitors, respectively. Kinases phosphorylate MAPKs, initiating and controlling the amplitude of the activation. In contrast, MAPK phosphatases (MKPs) dephosphorylate MAPKs, downregulating and controlling the duration of the signal. In addition, within the past decade, pseudoenzymes of these two families, pseudokinases and pseudophosphatases, have emerged as bona fide signaling regulators. This review discusses the role of pseudophosphatases in MAPK signaling, highlighting the function of phosphoserine/threonine/tyrosine-interacting protein (STYX) and TAK1-binding protein (TAB 1) in regulating MAPKs. Finally, a new paradigm is considered for this well-studied cellular pathway, and signal transduction pathways in general.

Keywords: MAPK phosphatase (MKP); MAPK phosphoserine/threonine/tyrosine-binding protein (MK-STYX); TAK1-binding protein (TAB 1); dual-specificity phosphatases (DUSPs); extracellular signal-regulated kinase (ERK); kinase; mitogen-activated protein kinase (MAPK); phosphoserine/threonine/tyrosine-interacting protein (STYX); protein tyrosine phosphatases (PTPs); pseudophosphatase.

Publication types

  • Review

MeSH terms

  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • MAP Kinase Signaling System / genetics*
  • Mitogen-Activated Protein Kinase Phosphatases / genetics*
  • Phosphorylation / genetics*


  • Intracellular Signaling Peptides and Proteins
  • Mitogen-Activated Protein Kinase Phosphatases