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State of survival what is plasma core8/28/2023 ![]() ![]() In contrast to this role in post-endocytic receptor traffic, our recent studies identified a unique role for EHD1 in the pre-activation transport of newly-synthesized RTKs, CSF1 receptor 4 and EGFR 5 from the Golgi to the plasma membrane to enable their efficient ligand-induced signaling and biological responses. Among them, EHD1 has been investigated the most and is well-established to regulate the post-endocytic recycling of a variety of cell surface receptors back to the cell surface 1, 2, 3. Members of the EPS15 homology domain-containing (EHD) protein family (EHD1-4) of membrane-activated ATPases have emerged as key regulators of vesicular traffic along the endocytic pathway 1, 2, 3. Our findings define the RTK traffic regulation as a proximal mechanism of EHD1 overexpression-dependent oncogenesis that impinges on IGF-1R in EWS, supporting the potential of IGF-1R and EHD1 co-targeting. Conversely, EHD1 overexpression-dependent exaggerated oncogenic traits require IGF-1R expression and kinase activity. ![]() Mechanistically, we demonstrate a requirement of EHD1 for endocytic recycling and Golgi to plasma membrane traffic of IGF-1R to maintain its surface expression and downstream signaling. RTK antibody arrays identified IGF-1R as a target of EHD1 regulation in EWS. ShRNA-knockdown and CRISPR-knockout with mouse Ehd1 rescue established a requirement of EHD1 for tumorigenesis and metastasis. We establish that EHD1 is overexpressed in Ewing sarcoma (EWS), with high EHD1 mRNA expression specifying shorter patient survival. Overexpression of the EPS15 Homology Domain containing 1 (EHD1) protein has been linked to tumorigenesis but whether its core function as a regulator of intracellular traffic of cell surface receptors plays a role in oncogenesis remains unknown. ![]()
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