Disease relevance of STIM1

• The stromal interaction molecular 1 gene (STIM1) encodes a type I trans-membrane protein of unknown function, which induces growth arrest and degeneration of the human tumor cell lines G401 and RD but not HBL100 and CaLu-6, suggesting a role in the pathogenesis of rhabdomyosarcomas and rhabdoid tumors [1].
• STIM1 overexpression studies in G401 rhabdoid tumour, rhabdomyosarcoma and rodent myoblast cell lines causes growth arrest, consistent with a potential role as a tumour growth suppressor [2].
• STIM1 (where STIM is stromal interaction molecule) is a candidate tumour suppressor gene that maps to human chromosome 11p15.5, a region implicated in a variety of cancers, particularly embryonal rhabdomyosarcoma [3].
• Similar analyses of human Wilms' tumor and normal kidney tissues demonstrated biallelic expression of STIM1 in the majority of samples [4].
• The expression of GOK, a gene recently identified at 11p15.5, was studied in breast cancer, rhabdomyosarcoma, and rhabdoid tumor cell lines [5].

Psychiatry related information on STIM1

• Such cognitive functions as attention, memory, executive function and problem solving were evaluated using subtests of STIM [6].

High impact information on STIM1

• STIM1, the putative calcium sensor in the endoplasmic reticulum, and the calcium release-activated calcium (CRAC) modulator CRACM1 (also known as Orai1) in the plasma membrane have recently been shown to be essential for controlling the store-operated CRAC current (I(CRAC)) [7].
• Overexpression of both proteins greatly potentiates I(CRAC), suggesting that STIM1 and CRACM1 mutually limit store-operated currents and that CRACM1 may be the long-sought CRAC channel [7].
• Ca2+ store depletion causes STIM1 to accumulate in ER regions closely associated with the plasma membrane [8].
• CRAC channels open only in the immediate vicinity of STIM1 puncta, restricting Ca(2+) entry to discrete sites comprising a small fraction of the cell surface [9].
• Stromal interacting molecule 1 (STIM1), reported to be an endoplasmic reticulum (ER) Ca(2+) sensor controlling store-operated Ca(2+) entry, redistributes from a diffuse ER localization into puncta at the cell periphery after store depletion [8].

Biological context of STIM1

• Mutants in the EF hand and cytoplasmic C terminus of STIM1 alter operational parameters of CRAC channels, including pharmacological profile and inactivation properties [10].
• As a cell surface signaling protein, STIM1 represents a key pharmacological target to control fundamental Ca(2+)-regulated processes including secretion, contraction, metabolism, cell division, and apoptosis [10].
• Introducing a point mutation in the STIM1 Ca(2+) binding domain resulted in prelocalization of the protein in puncta, and this mutant failed to respond to store depletion [11].
• The genetic tools developed in the present work will help to determine whether pathogenetic mechanisms that associate STIM1 with tumorigenesis involve mutations in coding sequences and/or promoter, and whether methylation could determine STIM1 transcriptional down-regulation in tumor samples [1].
• Here, we describe the STIM1 genomic organization including the identification of the promoter region [1].

Anatomical context of STIM1

• STIM1 has a plasma membrane role in the activation of store-operated Ca(2+) channels [10].
• STIM2 is expressed ubiquitously in cell lines, and co-precipitates with STIM1 from cell lysates [3].
• We have confirmed that STIM1 is modified by N-linked glycosylation at two sites within the SAM domain itself, deduced as asparagine residues N131 and N171, demonstrating that STIM1 is translocated across the membrane of the endoplasmic reticulum such that the SAM domain resides within the endoplasmic reticulum (ER) lumen [12].
• We used highly specific antibodies to show by immunofluorescence and cell surface biotinylation studies that STIM1 is located at the cell surface of K562 cells [2].
• All three proteins were co-localized in the plasma membrane region of cells, and thapsigargin increased co-immunoprecipitation of TRPC1 with STIM1, and Orai1 in human salivary gland cells as well as dispersed mouse submandibular gland cells [13].

Associations of STIM1 with chemical compounds

• Phosphorylation of STIM1 in vivo occurs predominantly on serine residues [2].
• Stromal interaction molecule 1 (STIM1) is a cell surface transmembrane glycoprotein implicated in tumour growth control and stromal-haematopoietic cell interactions [12].
• The opposing functions of STIM1 and STIM2 suggest they may play a coordinated role in controlling SOC-mediated Ca(2+) entry signals [14].
• STIM1, a single spanning membrane protein with an unpaired Ca(2+) binding EF-hand functions as the sensor of ER luminal Ca(2+) and through redistribution in the ER transduces information directly to the PM [15].
• CONCLUSION: Here we show that STIM1 acts as a key signal for SOC activation following intracellular Ca2+ store depletion or following agonist stimulation with histamine in human airway myocytes [16].
• This inhibition was significantly reversed in cells overexpressing EYFP-STIM1, implying that the primary inhibitory effect of nocodazole is related to STIM1 function [17].
• Sequestration of membrane cholesterol attenuated thapsigargin-induced clustering of STIM1 as well as SOCE in HSG and HEK293 cells [18].

Physical interactions of STIM1

• Direct Ca(2+) entry into the store is regulated by its filling status in a negative and positive manner through a Ca(2+)-binding protein and Stim1/Orai complex, respectively [19].

Regulatory relationships of STIM1

• Store depletion induces redistribution of STIM1 into distinct "puncta." STIM2 translocates into puncta upon store depletion only when coexpressed with STIM1 [14].
• Aggregation of STIM1 underneath the plasma membrane induces clustering of Orai1 [20].

Other interactions of STIM1

• Here, we monitored receptor-triggered Ca(2+) signals in cells transfected with siRNAs against 2,304 human signaling proteins, and we identified two proteins required for Ca(2+)-store-depletion-mediated Ca(2+) influx, STIM1 and STIM2 [11].
• However, these experiments did not establish whether Orai is an essential intracellular link between STIM and the CRAC channel, an accessory protein in the plasma membrane, or an actual pore subunit [21].
• Restriction mapping by pulsed-field electrophoresis indicates that GOK is located 1.7 kb telomeric of RRM1, and both genes are transcribed in the same direction [22].
• A novel gene (GOK) has been cloned from human chromosome region 11p15.5 that is believed to contain a gene or genes associated with a number of pediatric malignancies, including Wilms tumor [22].

Analytical, diagnostic and therapeutic context of STIM1

• Western blot analysis revealed that the 90-kDa STIM1 protein is ubiquitously expressed in various human primary cells and tumour cell lines [2].
• Fluorescence quenching and electron microscopy analysis reveal that puncta correspond to STIM1 accumulation in discrete subregions of junctional ER located 10-25 nm from the PM, without detectable insertion of STIM1 into the PM [8].
• Molecular cloning of a novel human gene (D11S4896E) at chromosomal region 11p15.5 [22].
• Activation was by "maximal" voluntary effort or by transcutaneous tetanic electrical stimulation that induced an isometric torque equal to 60% (STIM 1) or 45% (STIM 2) of the voluntary isometric value [23].
• Patients were tested during medication off/stimulation off (STIM OFF), medication off/stimulation on (STIM ON), and during the best motor state after taking levodopa without deep brain stimulation (MED) [24].

References