Calcineurin is a serine/threonine protein phosphatase that plays a critical role in many physiologic processes such as T-cell activation, skeletal myocyte differentiation, and cardiac hypertrophy. We previously showed that active MEKK3 is capable of stimulating calcineurin/nuclear factor of activated T-cells (NFAT) signaling in cardiac myocytes through phosphorylation of modulatory calcineurininteracting protein 1 (MCIP1). However, the protein kinases that function downstream of MEKK3 to mediate MCIP1 phosphorylation and the mechanism of MCIP1-mediated calcineurin regulation have not been defined. Here, we show that MEK5 and big MAP kinase 1 (BMK1) function downstream of MEKK3 in a signaling cascade that induces calcineurin activity through phosphorylation of MCIP1. Genetic studies showed that BMK1-deficient mouse lung fibroblasts failed to mediate MCIP1 phosphorylation and activate calcineurin/NFAT in response to angiotensin II, a potent NFAT activator. Conversely, restoring BMK1 to the deficient cells restored angiotensin II-mediated calcineurin/NFAT activation. Thus, using BMK1-deficient mouse lung fibroblast cells, we provided the genetic evidence that BMK1 is required for angiotensin II-mediated calcineurin/NFAT activation through MICP1 phosphorylation. Finally, we discovered that phosphorylated MCIP1 dissociates from calcineurin and binds with 14-3-3, thereby relieving its inhibitory effect on calcineurin activity. In summary, our findings reveal a previously unrecognized essential regulatory role of mitogen-activated protein kinase signaling in calcineurin activation through the reversible phosphorylation of a calcineurin-interacting protein, MCIP1.
Background and Purpose : Pre-hospital evaluation using telemedicine (TM) may accelerate acute stroke treatment with tissue plasminogen activator (t-PA). We explored the feasibility and reliability of using TM in the field and ambulance to help evaluate acute stroke patients. Methods : Ten unique, scripted stroke scenarios, each conducted four times, were portrayed by trained actors retrieved and transported by Houston Fire Department emergency medical technicians (EMT) to our stroke center. The vascular neurologists (VN) performed remote assessments in real-time, obtaining clinical data points and NIH Stroke-Scale (NIHSS) using the In-Touch RP-Xpress TM device. Each scripted scenario was recorded for a subsequent evaluation by a second blinded VN. Study feasibility was defined by the ability to conduct 80% of the sessions without major technological limitations. Reliability of video interpretation was defined by a 90% concordance between the data derived during the real-time sessions and the scripted scenarios. Results In 34/40 (85%) scenarios, the teleconsultation was conducted without major technical complication. The absolute agreement for intra-class-correlation (ICC) was 0.997 (95% CI: 0.992-0.999) for the NIHSS obtained during the real-time sessions and 0.993 (95% CI: 0.975-0.999) for the recorded sessions. Inter-rater agreement using κ-statistics showed that for live-raters, 10/15 items on the NIHSS showed excellent agreement, and 5/15 showed moderate agreement. Matching of real-time assessments occurred for 88% (30/34) of NIHSS scores by ±2 points, and 96% of the clinical information. Conclusions Mobile TM is reliable and feasible in assessing actors simulating acute stroke in the pre-hospital setting.
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