Kavli Affiliate: Jose Suarez Lopez
| Authors: Sukanya Chakraborty, Aaqib M. Bhat, Insha Mushtaq, Haitao Luan, Achyuth Kalluchi, Sameer Mirza, Matthew D. Storck, Nagendra Chaturvedi, Jose Antonio Lopez-Guerreo, Antonio Llombart-Bosch, Isidro Machado, Jane L. Meza, Gargi Ghosal, Donald W. Coulter, Jordan M. Rowley, Vimla Band, Bhopal C. Mohapatra and Hamid Band
| Summary:
We previously established a requirement of the EPS15 Homology Domain containing 1 (EHD1) protein in optimal cell surface expression and physiological signaling of receptor tyrosine kinase (RTKs), but any contribution of this mechanism to oncogenesis is unknown. Here, we show that EHD1 is overexpressed in Ewing sarcoma (EWS), with high EHD mRNA expression specifying shorter patient survival. ShRNA and CRISPR-knockout with mouse Ehd1 rescue establish a requirement of EHD1 for tumorigenesis and metastasis. RTK antibody arrays identified IGF-1R as a target of EHD1 regulation. 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. Conversely, EHD1-dependent exaggerated EWS oncogenic traits require IGF-1R expression and kinase activity. Our findings define the EHD1-dependent RTK traffic regulation as a novel pro-oncogenic mechanism that impinges on IGF-1R in EWS, supporting potential IGF-1R and EHD1 co-targeting.