title: Endogenous inhibitor proteins that connect Ser/Thr kinases and phosphatases in cell signaling.
abstract: Protein phosphatase activity acts as a primary determinant of the extent and duration of phosphorylation of cellular proteins in response to physiological stimuli. Ser/Thr protein phosphatase-1 (PP1) belongs to the PPP superfamily, and is associated with regulatory subunits that confer substrate specificity, allosteric regulation, and subcellular compartmentalization. In addition, all eukaryotic cells contain multiple heat-stable proteins that originally were thought to inhibit phosphatase catalytic subunits released from the regulatory subunits, as a fail-safe mechanism. However, discovery of C-kinase-activated PP1 inhibitor, Mr of 17 kDa (CPI-17) required fresh thinking about the endogenous inhibitors as specific regulators of particular phosphatase complexes, acting in addition to, not instead of, regulatory subunits. The cellular actions of the endogenous inhibitors are controlled by phosphorylation, connecting them to kinase pathways. More recent progress has unveiled additional functions of PP1 inhibitor-2 (I-2), including regulation of protein kinases. Transcriptional mechanisms govern the expression levels of CPI-17 in response to stimuli. If true for other inhibitor proteins, they have the potential of being diagnostic markers for pathological conditions. We discuss specific examples of PP1 inhibitor proteins regulating particular cellular functions and the rationale for incorporating phosphatase inhibitor proteins in development of new therapeutic strategies.
authors: Department of Molecular Physiology and Biophysics, and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. masumi.eto@jefferson.edu
authors: Masumi
authors: M
authors: Eto
authors: David L
authors: DL
authors: Brautigan
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases