EGFR and Calmodulin Signalling group


In the last years our research interest is the study of the traffic and signalling of the epidermal growth factor receptor (EGFR) regulated by calmodulin (CaM) and protein kinase C delta (PKCδ). The endocytosis of the EGFR depends on the binding to EGF and its later activation. This process causes the reduction of the 90% of the total of cellular receptors by a mechanism dependent on ubiquitinization and targeting of EGF-EGFR complexes to lisosomes to be degraded.

The regulation of the cellular levels of the EGFR is of enormous interest since an overxpression or a deficient endocytosis of the receptor, which lead to an excessive and not regulated signalling, occur in different types of cancer. EGFR and small protein GTPases Rac1, KRas and HRas regulate important cellular processes such as endocytosis, proliferation, apoptosis or migration. To determine the signaling regulation of these proteins becomes more relevant as they are frequently overexpressed or mutated in cancer and other diseases.


In the last years the functions of these proteins has been related to their signaling in the endosomes. It has been reported that EGFR signaling in endosomes is involved in cell cycle progression and contributes to survival and cell proliferation. The endocytic compartment represents a functional continuity of the plasma membrane and allowed to persist and continue signaling generated in the plasma membrane. It acts as a specific signaling platform. Endosomes by interaction with the cytoskeleton allow the traffic of signaling molecules to different cellular locations and are involved in the degradation of signaling complexes directing them to the lysosomes.


The presence of Rac1, H-and K-Ras in endosomes has been well established. In fact, we have reported that KRas is found in the endocytic compartment and that its association is induced by EGF. Our interest is focused mainly to determine the relevance of Rac1 and KRas signaling regulated by EGFR in the endocytic compartment to control cellular processes such as proliferation, motility, migration or self-regulation of maturation, location and mobility of endosomes.


On the other hand, we recently reported that Rac1 is a CaM-binding protein and the hypervariable region and the state of activation of Rac1 are required for binding to CaM. Inhibiting CaM or the overexpression of the dominant negative mutant of Rac1 induced, through PIP5K, the formation of Arf6 and PI4, 5P2 positive membrane tubulations. By contrast, the expression of constitutively active mutant of Rac1 prevents them. Our aim is to analyze the molecular machinery involved in the formation and/or scission of such endocytic tubulations regulated by Rac1 and CaM.

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