The clinical significance of STIM proteins and Orai Ca2+ channels in tumor progression has been demonstrated in different types of cancers. Podosomes are dynamic actin-rich cellular protrusions that facilitate cancer cell invasiveness by degrading extracellular matrix. Whether STIM1-dependent Ca2+ signaling facilitates cancer cell invasion through affecting podosome formation remains unclear. Here we show that the invasive fronts of cancer tissues overexpress STIM1, accompanied by active store-operated Ca2+ entry (SOCE). Interfering SOCE activity by SOCE inhibitors and STIM1 or Orai1 knockdown remarkably affects podosome rosettes formation. Mechanistically, STIM1-silencing significantly alters the podosome rosettes dynamics, shortens the maintenance phase of podosome rosettes and reduces cell invasiveness. The subsequently transient expression of STIM1 cDNA in STIM1-null (STIM1−/−) mouse embryo fibroblasts rescues the suppression of podosome formation, suggesting that STIM1-mediated SOCE activation directly regulates podosome formation. This study uncovers SOCE-mediated Ca2+ microdomain that is the molecular basis for Ca2+ sensitivity controlling podosome formation.

Carbon dioxide (CO 2 ) is a fundamental physiological gas known to profoundly influence the behaviour and health of millions of species within the plant and animal kingdoms in particular. A recent Royal Society meeting on the topic of ‘Carbon dioxide detection in biological systems' was extremely revealing in terms of the multitude of roles that different levels of CO 2 play in influencing plants and animals alike. While outstanding research has been performed by leading researchers in the area of plant biology, neuronal sensing, cell signalling, gas transport, inflammation, lung function and clinical medicine, there is still much to be learned about CO 2 -dependent sensing and signalling. Notably, while several key signal transduction pathways and nodes of activity have been identified in plants and animals respectively, the precise wiring and sensitivity of these pathways to CO 2 remains to be fully elucidated. In this article, we will give an overview of the literature relating to CO 2 -dependent signal transduction in mammalian systems. We will highlight the main signal transduction hubs through which CO 2 -dependent signalling is elicited with a view to better understanding the complex physiological response to CO 2 in mammalian systems. The main topics of discussion in this article relate to how changes in CO 2 influence cellular function through modulation of signal transduction networks influenced by pH, mitochondrial function, adenylate cyclase, calcium, transcriptional regulators, the adenosine monophosphate-activated protein kinase pathway and direct CO 2 -dependent protein modifications. While each of these topics will be discussed independently, there is evidence of significant cross-talk between these signal transduction pathways as they respond to changes in CO 2 . In considering these core hubs of CO 2 -dependent signal transduction, we hope to delineate common elements and identify areas in which future research could be best directed.