In this review, we first describe the mechanisms by which the epidermal growth factor receptor generates a Ca2+ signal and, subsequently, we compile the available experimental evidence regarding the role that the Ca2+/calmodulin complex, formed after the rise in cytosolic free Ca2+ concentration, exerts on the receptor. We focus not only on the indirect action that Ca2+/calmodulin exerts on the epidermal growth factor receptor, as a result of the activation of distinct calmodulin‐dependent kinases, but also, and more extensively, on the direct interaction of Ca2+/calmodulin with the receptor. We also describe several mechanistic models that could account for the Ca2+/calmodulin‐mediated regulation of epidermal growth factor receptor activity. The control exerted by calmodulin on distinct epidermal growth factor receptor‐mediated cellular functions is also discussed. Finally, the phosphorylation of this Ca2+ sensor by the epidermal growth factor receptor is highlighted.

Background:The EGFR binds calmodulin (CaM). Results: CaM antagonists, CaM down-regulation in conditional CaM-KO cells, chelation of Ca 2ϩ , and mutagenesis of the CaM-binding domain inhibit EGFR activation. Conclusion: The Ca 2ϩ /CaM complex is a positive regulator of the EGFR. Significance: This is the first work with a multi-approach strategy demonstrating that CaM directly regulates the EGFR in living cells.

Background: Calmodulin is a Ca 2ϩ binding protein and a major regulator of multiple signaling pathways. Results: Inactivation of the Ca 2ϩ binding sites in the N-and C-terminal lobe of CaM affects cell viability differentially. Conclusion: Ca 2ϩ binding to CaM is required for vertebrate cell survival. Significance: A novel vertebrate knock-out/knock-in system for studying the function of CaM is described.

ObjectiveTo analyse the association in newborns between blood levels of phenylalanine and feeding method and gestational age.Study DesignThis observational, cross-sectional study included a sample of 11,829 infants between 2008 and 2013 in a Spanish region. Data were recorded on phenylalanine values, feeding method [breast, formula, mixed (breast plus formula), or partial or fully intravenous feeding], gestational age in weeks (<32, 32–37, ≥37), gender and days since birth at the moment of blood collection. Outcomes were [phenylalanine] and [phenylalanine] ≥95th percentile. Associations were analysed using multivariate models [linear (means difference) and logistic regression (adjusted odds ratios)].ResultsHigher phenylalanine values were associated with lower gestational age (p<0.001) and with intravenous feeding (p<0.001).ConclusionThe degree of prematurity and intravenous feeding influenced the plasma concentration of phenylalanine in the newborn. Caution should be taken in [phenylalanine] for newborns with intravenous feeding, monitoring them carefully. Very preterm infants given the recommended amount of amino acids should also be strictly monitored. These findings should be taken into consideration and call for adapting the amounts to the needs of the infant.