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Graf regulates hematopoiesis through GEEC endocytosis of EGFR

Title
Graf regulates hematopoiesis through GEEC endocytosis of EGFR
Author
심지원
Keywords
Graf; GEEC endocytosis; EGFR; D-Cbl-mediated receptor ubiquitination; Plasmatocyte proliferation; Drosophila
Issue Date
2017-10
Publisher
COMPANY OF BIOLOGISTS LTD
Citation
DEVELOPMENT, v. 144, no. 22, page. 4159-4172
Abstract
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.
URI
https://dev.biologists.org/content/144/22/4159https://repository.hanyang.ac.kr/handle/20.500.11754/115897
ISSN
0950-1991; 1477-9129
DOI
10.1186/s40557-017-0203-y
Appears in Collections:
COLLEGE OF NATURAL SCIENCES[S](자연과학대학) > LIFE SCIENCE(생명과학과) > Articles
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