Emerging roles of the single EF-hand Ca2+ sensor tescalcin in the regulation of gene expression, cell growth and differentiation

Abstract

Tescalcin (TESC, also known as calcineurin-homologous protein 3, CHP3) is a 24-kDa EF-hand Ca²⁺-binding protein that has recently emerged as a regulator of cell differentiation and growth. The TESC gene has also been linked to human brain abnormalities, and high expression of tescalcin has been found in several cancers. The expression level of tescalcin changes dramatically during development and upon signal-induced cell differentiation. Recent studies have shown that tescalcin is not only subjected to up- or down-regulation, but also has an active role in pathways that drive cell growth and differentiation programs. At the molecular level, there is compelling experimental evidence showing that tescalcin can directly interact with and regulate the activities of the Na⁺/H⁺ exchanger NHE1, subunit 4 of the COP9 signalosome (CSN4) and protein kinase glycogen-synthase kinase 3 (GSK3). In hematopoetic precursor cells, tescalcin has been shown to couple activation of the extracellular signal-regulated kinase (ERK) cascade to the expression of transcription factors that control cell differentiation. The purpose of this Commentary is to summarize recent efforts that have served to characterize the biochemical, genetic and physiological attributes of tescalcin, and its unique role in the regulation of various cellular functions.

Keywords: CHP3; COP9; Differentiation; GSK3; NHE1; Tescalcin.

Fig. 1.

Sequences of tescalcin and its close homologs. Shown here are the amino acid sequences human tescalcin (Genbank Accession Number AAL35615.1) with CHP1 (NP_009167), CHP2 (NP_071380.1) and calcineurin B (CnB, AAB08721.1). Sequence alignment was performed using ClustalW, with BoxShage 3.21 for presentation. Identical amino acids are shown in dark green; homologous residues are in teal. The four active EF-hand domains in CnB are denoted by blue brackets and are numbered. The solid bracket surrounding the canonical EF-hand 3 indicates that it is active in tescalcin. The red arrow indicates the position of the critical D123 residue necessary for Ca²⁺ binding; the D123A mutant has been used to study the role of Ca²⁺ in tescalcin function (see text). The dashed brackets show the EF-hands that are inactive in tescalcin. EF-hand 4 is active in CHP1 and CHP2. The unique amino acid ‘inserts’ found in tescalcin are highlighted with red frames; these interrupt the sequences in its homologous EF-hand domains 2 and 4. The N-myristoylation site, the G2 residue, is indicated by the arrow.

Fig. 2.

Protein–protein interactions and biological activities of tescalcin. Tescalcin modulates the activities of NHE1, the Cop9 signalosome and the AKT–GSK3 axis. It interacts directly with NHE1, increasing its stability and the rate of exchange of Na⁺ for H⁺ ions, which leads to elevation of intracellular pH (pH_i). Tescalcin has also been shown to interact with the CSN4 (and CSN5) subunit of the signalosome which affects many processes including degradation of proteins involved in cell cycle. Finally, tescalcin interacts with the protein kinases AKT and GSK3, which have multiple substrates and a number of known mechanisms of activation, e.g. through insulin receptor (InsR), which has been shown to activate GSK3 in a tescalcin-dependent manner (see text). Each of these pathways has many downstream effectors, including cell-type-specific transcription factors. The level of tescalcin expression is regulated by ERK1/2 (brown arrow) through an unknown mechanism; it can be up- or down-regulated depending on the cell type. ERK1/2 can be activated by PKC, receptor tyrosine kinases (RTKs) and other mechanisms. The interaction of tescalcin with NHE1 and CSN4, but not that with AKT and/or GSK3, requires Ca²⁺. Depending on the cell type, the physiological effects include cell cycle arrest and differentiation, or growth. Furthermore, genetic evidence has implicated the tescalcin gene (TESC) in cancer and developmental abnormalities (see text).