Research Highlights

February 07, 2019

BMP-dependent synaptic development requires Abi-Abl-Rac signaling of BMP receptor macropinocytosis

Najin Kim, Sungdae Kim, Minyeop Nahm, Danielle Kopke, Joohyung Kim, Eunsang Cho, Min-Jung Lee, Mihye Lee, Seung Hyun Kim, Kendal Broadie & Seungbok Lee

Nature Communications. 2019 Feb 8;10(1):684. doi: 10.1038/s41467-019-08533-2.


Retrograde BMP trans-synaptic signaling is essential for synaptic development. Despite the importance of endocytosis-regulated BMP receptor (BMPR) control of this developmental signaling, the mechanism remains unknown. Here, we provide evidence that Abelson interactor (Abi), a substrate for Abl kinase and component of the SCAR/WAVE complex, links Abl and Rac1 GTPase signaling to BMPR macropinocytosis to restrain BMP-mediated synaptic development. We find that Abi acts downstream of Abl and Rac1, and that BMP ligand Glass bottom boat (Gbb) induces macropinocytosis dependent on Rac1/SCAR signaling, Abl-mediated Abi phosphorylation, and BMPR activation. Macropinocytosis acts as the major internalization route for BMPRs at the synapse in a process driven by Gbb activation and resulting in receptor degradation. Key regulators of macropinocytosis (Rabankyrin and CtBP) control BMPR trafficking to limit BMP trans-synaptic signaling. We conclude that BMP-induced macropinocytosis acts as a BMPR homeostatic mechanism to regulate BMP-mediated synaptic development.

October 01, 2017

Graf regulates hematopoiesis through GEEC endocytosis of EGFR.

Sungdae Kim, Minyeop Nahm, Najin Kim, Yumi Kwon, Joohyung Kim, Sukwoo Choi, Eun Young Choi, Jiwon Shim, Cheolju Lee, Seungbok Lee

Development 2017 144: 4159-4172


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 GRAF1gene 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.

February 19, 2013

Spartin Regulates Synaptic Growth and Neuronal Survival by Inhibiting BMP-Mediated Microtubule Stabilization

Minyeop Nahm, Min-Jung Lee, William Parkinson, Mihye Lee, Haeran Kim, Yoon-Jung Kim, Sungdae Kim, Yi Sul Cho, Byung-Moo Min, Yong Chul Bae, Kendal Broadie, Seungbok Lee

Neuron Volume 77, Issue 4, p680–695, 20 February 2013


Troyer syndrome is a hereditary spastic paraplegia caused by human spartin(SPG20) gene mutations. We have generated a Drosophila disease model showing that Spartin functions presynaptically with endocytic adaptor Eps15 to regulate synaptic growth and function. Spartin inhibits bone morphogenetic protein (BMP) signaling by promoting endocytic degradation of BMP receptor wishful thinking (Wit). Drosophila fragile X mental retardation protein (dFMRP) and Futsch/MAP1B are downstream effectors of Spartin and BMP signaling in regulating microtubule stability and synaptic growth. Loss of Spartin or elevation of BMP signaling induces age-dependent progressive defects resembling hereditary spastic paraplegias, including motor dysfunction and brain neurodegeneration. Null spartin phenotypes are prevented by administration of the microtubule-destabilizing drug vinblastine. Together, these results demonstrate that Spartin regulates both synaptic development and neuronal survival by controlling microtubule stability via the BMP-dFMRP-Futsch pathway, suggesting that impaired regulation of microtubule stability is a core pathogenic component in Troyer syndrome.

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