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Researchers in the Department of Physiology, Anatomy and Genetics publish in the prestigious Molecular Cell an article entitled "Distinct Spatial Ca2+ Signatures Selectively Activate Different NFAT Transcription Factor Isoforms"

Many proteins have multiple isoforms that are often co-expressed in the same cell. Examples include ion channels, metabolic enzymes, kinases and transcription factors that regulate gene expression. Isoforms can arise from different genes or through alternative splicing of the same gene. Protein isoforms are ubiquitous in nature. The fact that green algae, yeast, Caenorhabditis elegans and vertebrates all express several protein isoforms reinforces the view that this tight evolutionary conservation underlies important, isoform-specific biological function.

A critical question in cell biology is therefore how some isoforms can be activated and not others when several are co-expressed within the same cell. A partial answer has been provided by the finding that isoforms of protein kinases are corralled to different sub-cellular locations, controlling only those substrates constrained within the immediate vicinity. However, many protein isoforms share the same spatial domain and are activated by the same intracellular messenger. How can one isoform now be activated selectively and how might it gain access to targets that other isoforms are excluded from? This issue is nicely encapsulated by the NFAT family of transcription factors, which are essential for vertebrate development, differentiation and function. NFAT proteins share the same spatial and temporal domain and are activated by the same intracellular signal, a rise in cytoplasmic Ca2+. How can different NFAT proteins be selectively activated?

Professor Anant Parekh’s group in DPAG have directly addressed this question, comparing the closely related NFAT1 and NFAT4 isoforms. Their new findings, published in this month’s Molecular Cell (58, 232-243), demonstrate that NFAT1 has a private line of communication with plasma membrane calcium channels, activating in response to Ca2+ microdomains near the open channels. By contrast NFAT4 is more of a co-incidence detector, requiring both local Ca2+ entry through the same channels as well as a rise in nuclear Ca2+. These different Ca2+-dependencies enable agonist to recruit different isoform combinations as stimulus strength increases. The results identify a new mechanism that enables selective activation of closely related proteins within the same cell. “This is a novel mechanism that enables a physiological trigger to recruit different transcription factors in a manner determined by stimulus intensity”, said Dr Kar. Professor Parekh added: “Differential recruitment of subtly distinct signaling molecules increases the temporal bandwidth for information processing in a biological system”. Professor Gill and colleagues from Pennsylvania, USA, have written a commentary in Molecular Cell (58, 197-199) that accompanies the article.

More information on the Molecular Cell website

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