STIM proteins: integrators of signalling pathways in development, differentiation and disease

Abstract

The stromal interaction molecules STIM1 and STIM2 are endoplasmic reticulum Ca(2+) sensors, serving to detect changes in receptor-mediated ER Ca(2+) store depletion and to relay this information to plasma membrane localized proteins, including the store-operated Ca(2+) channels of the ORAI family. The resulting Ca(2+) influx sustains the high cytosolic Ca(2+) levels required for activation of many intracellular signal transducers such as the NFAT family of transcription factors. Models of STIM protein deficiency in mice, Drosophila melanogaster and Caenorhabditis elegans, in addition to the phenotype of patients bearing mutations in STIM1 have provided great insight into the role of these proteins in cell physiology and pathology. It is now becoming clear that STIM1 and STIM2 are critical for the development and functioning of many cell types, including lymphocytes, skeletal and smooth muscle myoblasts, adipocytes and neurons, and can interact with a variety of signalling proteins and pathways in a cell- and tissue-type specific manner. This review focuses on the role of STIM proteins in development, differentiation and disease, in particular highlighting the functional differences between STIM1 and STIM2.

Fig 1

Illustration of the structural domains in vertebrate STIM1 and STIM2 proteins, D, melanogaster D-Stim and C. elegans C-Stim. A signal peptide (SP) and transmembrane domain (TM) flank EF hand and SAM domain, coiled coils (CC1, 2), and position of CRAC activating domain (CAD) [32] within an ERM domain, proline-righ region (PR) and lysine-rich tail at the C-terminus (KK). A pair of cysteine residues near the N-terminus (cc) and the proximal N-linked glycosylation site (hexagon) are not conserved in C-Stim. The distal glycosylation site is present only in C-Stim and STIM1. A unique protein sequence containing no known structural domains is present in D-Stim (X). Modified from [37]).

Fig 2

Immunofluorescent staining of myosin heavy chain (MHC) in fixed C2C12 cells overexpressing STIM1. Cells transiently overexpressing STIM1 or empty vector were fixed at day 6 after induction of differentiation and immunostained for MHC (green) and DAPI (blue) to identify myotubes (mt). The experiment was performed in duplicate. The differentiation index (percentage of nuclei associated with MHC) was calculated by analysing 16 fields of view per group. Vector – 40.2%, STIM1 – 59.7% (P= 0.009).

Fig 3

Haematoxylin and eosin stained sections of subcutaneous tumours derived from STIM1 or STIM2 overexpressing PC12 cells injected into nude mice. Control (vector) PC12 tumour cells (t) are aligned against connective tissue and skeletal muscle fibres (m) of the body wall, with only very limited infiltration of cells between muscle fibres seen in two of nine tumours. In STIM1 (n= 9) and STIM2 (n= 9) tumours, invasive tumour-derived cells have infiltrated between skeletal muscle fibres (m), with extensive infiltration evident in >50% of tumours of both types.