Biology subjects

Reed, D. K.

Publications and source records attributed to Reed, D. K..

2 recordsLinked to original sources

bioRxiv2024

Caveolin-1 regulates context-dependent signaling and survival in Ewing Sarcoma.

Plasticity is a hallmark function of cancer cells, yet the mechanisms that enable dynamic switching between survival states remain incompletely understood. Here, we identify Caveolin-1, a membrane-domain scaffolding protein, as a context-dependent regulator of survival signaling in Ewing sarcoma (EwS). Single-cell analyses reveal a distinct subpopulation of EwS cells marked by high CD99 and elevated Caveolin-1 expression. These CD99High cells exhibit unique morphology, transcriptional programs, and markedly enhanced survival both under chemotherapeutic challenge and in vivo. Importantly, CD99High and CD99Low states are reversible, providing EwS cells with a flexible route to survival-oriented plasticity. Mechanistically, we show that Caveolin-1 in CD99High cells orchestrates PI3K/AKT survival signaling by modulating the spatial organization of PI3K activity on the plasma membrane. We propose that the CD99High state establishes a Caveolin-1-driven signaling architecture that supports survival through mechanisms distinct from those used by CD99Low cells. These findings uncover a dynamic state transition in EwS cells and position Caveolin-1 as a key driver of context-specific survival signaling.

cancer biology↗

bioRxiv2020

Structure-based inhibitors reveal roles for the clathrin terminal domain and its W-box binding site in CME

Clathrin-mediated endocytosis (CME) occurs via the formation of clathrin-coated vesicles from clathrin-coated pits (CCPs). Clathrin is recruited to CCPs through interactions between the AP2 complex and its N-terminal domain (TD), which in turn recruits endocytic accessory proteins. Inhibitors of CME that interfere with clathrin function have been described, but their specificity and mechanisms of action are unclear. Here we show that overexpression of the TD with or without the distal leg specifically inhibits CME and CCP dynamics by perturbing clathrin interactions with AP2 and SNX9. We designed small membrane-penetrating peptides that mimic the four known binding sites on the TD. A peptide, Wbox2, designed to mimic to the W-box motif binding surface on TD binds to SNX9 and AP2, and potently and acutely inhibits CME, while not perturbing AP1-dependent lysosomal trafficking from the Golgi or bulk, fluid phase endocytosis. SummaryChen et al define the role the N-terminal domain (TD) of clathrin heavy chain in early and late stages of clathrin-mediated endocytosis, and guided by its structure, design a membrane-penetrating peptide, Wbox2, that acutely and potently inhibits CME.

cell biology↗