STIM2 - STIM2 Function

STIM2 Function

The STIM2 function has been controversial and still is under discussion. First studies found that siRNA knockdown of STIM1, but not STIM2, strongly reduced SOCE in mammalian cells. Liou et al. reported a slight reduction in SOCE also by knockdown of STIM2 in HeLa cells. Soboloff et al. suggested that STIM2 inhibits SOCE when expressed alone, but coexpressed with Orai1 causes substantial constitutive SOCE. In contrast, Brandman et al. suggested that STIM2 could act as a regulator that stabilizes basal cytosolic and ER Ca2+ levels. Parvez et al., using in vitro transient coexpression of human STIM2 and different SOC channels in HEK293 cells, reported that STIM2 mediates SOCE via two store-dependent and store independent modes. Taking together, these results indicate a complex interaction finely regulated by the STIM1: STIM2: Orai cellular ratio and their endogenous levels. Studies performed in 2009-2010 using human in vitro or murine in vivo models confirmed Brandman et al. results and suggested that STIM2 participates in processes of the development and functioning of many cell types, including smooth muscle myoblasts, cells of the immune system and neurons. Moreover, it is involved in tumorigenesis, the development of autoimmune diseases and mechanisms of neuronal damage after transient ischemic conditions. In resting conditions, cultured HEK293 cells overexpressing or cortical neurons lacking STIM2 have increased or decreased resting intracellular Ca2+ levels respectively, supporting the idea that STIM2 is essential for regulation of intracellular basal Ca2+ levels. However, cells are very active in vivo and intracellular Ca2+ levels are continuously fluctuating. The development of new methods to study the in vivo role of STIM2 in intracellular Ca2+ levels would be necessary. In cultured human myoblast, STIM2 participate in cell differentiation into myotubes. In the immune system, STIM2 participates in T cell activation-induced production of interleukin2 (IL-2) and interferon gamma (IFN_γ), probably by stabilization of NFAT residence in the nucleus, as well as in differentiation of naive T cells into Th₁₇ lymphocytes, which presumably are important in early phases of autoimmune diseases. In fact, STIM2-deficient mice showed mild symptomatology in the early phase of autoimmune diseases. In neuronal tissue, STIM2 plays a crucial role in ischemia-induced neuronal damage, and the absence of STIM2 in knockout mice reduced the neuronal damage produced by ischemia after transient interruption of blood flow in brain. This neuroprotective effect of STIM2-deficiency after an ischemic episode indicates that inhibitors of STIM2 function may thus have a potential therapeutic value as neuroprotective agents to treat ischemic injury and other neurodegenerative disorders involving altered Ca2+ homeostasis. Moreover, the same scientific study suggested an important role of STIM2 in hippocampus-dependent spatial memory, synaptic transmission and plasticity. Finally, an oncogenic function has been demonstrated for STIM2, together with STIM1, in glioblastoma multiforme, where both proteins have increased expression and/or increased copy number. Additionally, STIM2 is located in chromosome 4p15.1, a region implicated in invasive carcinomas of the lung, breast, neck and head.