Regulatory Mechanism of EGFR-Mediated Oncogenic Signaling in Prostate Cancer Cells

摘要

The EGFR receptor tyrosine kinase is dysfunctional in a wide range of solid human tumors including prostate carcinomas. The EGFR gene product is a transmembrane glycoprotein belonging to the epidermal growth factor receptor family and its cytoplasmic domain is responsible for sending the mitogenic signals into cells. We discovered that this domain of EGFR interacts with Tid1 protein, a human counterpart of Drosophila tumor suppressor Tid56. Tid56 null mutation causes lethal tumorigenesis during larvae stage. Tid1 is also known as a cochaperone of the heat shock protein 70 (Hsp7O) and binds to Hsp7O through its conserved DnaJ-domain. We found that increased expression of Tid1 in human carcinoma attenuates the EGFR-dependent oncogenic ERKl/2 and BMKl signaling pathways. Importantly, the functional DnaJ-domain of Tid1 is required for consequent suppression of oncogenic signaling of carcinoma cells resulting from increased Tid1 expression. Together, these results suggest that Tid1 deterring uncontrolled proliferation of carcinoma cells through reducing the downregulating the cancerous signaling from EGFR. Moreover, the cochaperonic and regulatory function of Tid1 on Hsp7O most likely play an essential role of this anti- proliferation function of Tid1 in carcinoma cells.