EGFR and Calmodulin Signalling group

LINES OF RESEARCH

Role of PKCδ in the degradation of EGFR and LDL. Relevance in different types of tumors

Summary

The PKCδ activity is necessary for the efficient degradation of the EGF-EGFR complex. The degradation of the EGF-EGFR depends on its own signaling, its ubiquitinylation and the subsequent traffic of the receptor to the multivesicular bodies (MBVs) /lysosomes. The role of PKCδ in the different processes that participate in the degradation of the receptor will be analyzed. In a comparative way, the role of PKCδ in the degradation of LDL will also be studied. LDL is transported to the early endosomes by binding to its specific receptor, but it does not participate in the later transport of LDL to lysosomes. In addition, our interest is focused on the correlation between the levels of PKCδ and EGFR in the putative abnormal traffic of the EGFR in different tumour lines.

Description

The binding of EGF to its receptor (EGFR) activates multiple signaling pathways that control several cellular processes, such as mitosis, cell survival, differentiation and cell migration. Deregulation of these cellular processes can lead to tumor formation. Indeed, aberrant activity of EGFR is associated with many human cancers of poor prognosis. The binding of EGF induces receptor dimerization, activation of its tyrosine kinase activity and trans-autophosphorylation of tyrosine residues on its cytoplasmic tail that are binding sites for adapter proteins and enzymes through which activates various signaling pathways.

 

In turn, activation of the receptor induces the rapid internalization of EGF-EGFR complex mainly through clathrin coated pits. These complexes can be internalized and rapidly recycled from early endosomes to the plasma membrane or remain there during their maturation to late endosomes or multi-vesicular bodies (MVBs). The MVBs eventually fuse with the lysosomes and the EGF-EGFR complex is degraded. This is a key mechanism for the attenuation of EGFR signaling, known as "down-regulation" of the receptor.

 

We have found that inhibition of PKCδ causes a significant reduction in the EGF receptor degradation even though its internalization and recycling were not modified. Therefore, PKCδ may be involved in controlling cellular levels of EGFR. It should be noted that recently is emerging the conception of PKC as a tumor suppressor by its effects on actin dynamics and apoptosis. Although there is some controversy in this regard, PKCδ inhibits cell migration in breast cancer cells and primary cultures of fibroblasts. The results show that loss of PKCδ may contribute to survival and metastasis.

 

The main objective is to analyze the role of PKCδ on the trafficking of the EGFR and other molecules, like LDL, to the lysosomes. In addition, the correlation between the levels of PKCδ and EGFR in the putative abnormal traffic of the EGFR in different tumour lines will be analysed.

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