Kim, Sungdae Nahm, Minyeop Kim, Najin Kwon, Yumi Kim, Joohyung Choi, Sukwoo Choi, Eun Young Shim, Jiwon Lee, Cheolju Lee, Seungbok 2024-01-20T00:03:49Z 2024-01-20T00:03:49Z 2022-01-25 2017-11 0950-1991 https://pubs.kist.re.kr/handle/201004/122090 GTPase regulator associated with focal adhesion kinase 1 (GRAF1) is an essential component of the GPI-enriched endocytic compartment (GEEC) endocytosis pathway. Mutations in the human GRAF1 gene are associated with acute myeloid leukemia, but its normal role in myeloid cell development remains unclear. We show that Graf, the Drosophila ortholog of GRAF1, is expressed and specifically localizes to GEEC endocytic membranes in macrophage-like plasmatocytes. We also find that loss of Graf impairs GEEC endocytosis, enhances EGFR signaling and induces a plasmatocyte overproliferation phenotype that requires the EGFR signaling cascade. Mechanistically, Graf-dependent GEEC endocytosis serves as a major route for EGFR internalization at high, but not low, doses of the predominant Drosophila EGFR ligand Spitz (Spi), and is indispensable for efficient EGFR degradation and signal attenuation. Finally, Graf interacts directly with EGFR in a receptor ubiquitylation-dependent manner, suggesting a mechanism by which Graf promotes GEEC endocytosis of EGFR at high Spi. Based on our findings, we propose a model in which Graf functions to downregulate EGFR signaling by facilitating Spi-induced receptor internalization through GEEC endocytosis, thereby restraining plasmatocyte proliferation. English COMPANY OF BIOLOGISTS LTD Graf regulates hematopoiesis through GEEC endocytosis of EGFR Article 10.1242/dev.153288 1 DEVELOPMENT, v.144, no.22, pp.4159 - 4172 DEVELOPMENT 144 22 4159 4172 N scie scopus 000415069600010 2-s2.0-85034431908 Developmental Biology Developmental Biology Article ACUTE MYELOGENOUS LEUKEMIA GROWTH-FACTOR RECEPTOR CELL LUNG-CANCER INDEPENDENT ENDOCYTOSIS DROSOPHILA HEMOCYTES MYELOID-LEUKEMIA MLL/GRAF FUSION GENE PATHWAY BLOOD Graf GEEC endocytosis EGFR D-Cbl-mediated receptor ubiquitination Plasmatocyte proliferation Drosophila