Ethan Garvin

All Publications

• Mutational scanning reveals substrate-assisted autoregulation of the WNT destruction complex. Nature genetics Padmanarayana, M., Sakalas, S., Sarkar, P., Ma, M., Garvin, E. R., Lee, E., Corsello, S. M., Guettler, S., Pusapati, G. V., Rohatgi, R. 2026

  Abstract

  The β-catenin destruction complex (BDC) regulates WNT-β-catenin signaling and is a prime therapeutic target in colorectal cancer, yet its biochemical complexity has hindered mechanistic understanding. We mapped the sequence-function landscape of the BDC using tiled base editor screens across its components CTNNB1, AXIN1, APC and GSK3B. Amongst ~150 previously unreported mutations that affected WNT signaling, we discovered gain-of-function and separation-of-function alleles that reveal mechanisms of complex assembly, including a β-catenin region regulating TCF/LEF transcription factor binding. Critically, we found that the AXIN1-β-catenin interface controls signaling flux through the oncogenic BDC found in APC-mutant cancers. In cells expressing truncated APC, β-catenin itself scaffolds BDC assembly, establishing a substrate-assisted autoregulatory mechanism. This architecture represents an unexploited therapeutic vulnerability: strengthening the AXIN1-β-catenin interaction restores destruction complex function and impairs the growth of colorectal cancer cells. Our mutational resource provides a foundation for mechanistic understanding and therapeutic targeting of the WNT pathway.

  View details for DOI 10.1038/s41588-026-02662-3

  View details for PubMedID 42393221

  View details for PubMedCentralID 6070353

• The molecular basis for nuclear pore destruction by a proximity-inducing molecular glue. Cell chemical biology Hinshaw, S. M., Yuan, L., Noman, M. A., Martinez, M. J., Colombo, G. M., Dwyer, B. G., Ji, W., Romero, B. A., Forrest, I., Lu, J., Bian, J., Dunn, T. B., Garvin, E. R., Fernandez, D., Zhang, T., Gray, N. S., Corsello, S. M. 2026

  Abstract

  Molecular glues that induce new protein interactions can be potent therapeutics. We and others recently discovered that the small molecule PRLX-93936 (PRLX), which was originally developed as an erastin derivative with antitumor activity, is a molecular glue that alters the substrate specificity of the TRIM21 ubiquitin ligase. PRLX causes TRIM21 to bind the nuclear pore protein NUP98, triggering nuclear pore complex (NPC) degradation. We present here the structural and biochemical basis of NUP98 recognition, finding that ternary complex assembly depends on the creation of a composite TRIM21-small molecule surface competent for NUP98 binding. A scarcity of direct small molecule-NUP98 contacts likely explains how multiple structurally diverse TRIM21 ligands can induce NPC degradation. We also report the discovery of an enhanced molecular glue, MAN-021, and describe its structure. Our findings provide a basis for rational development of next-generation small molecules with enhanced or differentiated activities.

  View details for DOI 10.1016/j.chembiol.2026.04.016

  View details for PubMedID 42202785

• Mutational scanning reveals substrate-assisted autoregulation of the WNT destruction complex. bioRxiv : the preprint server for biology Padmanarayana, M., Sakalas, S., Sarkar, P., Ma, M., Garvin, E. R., Lee, E., Corsello, S. M., Guettler, S., Pusapati, G. V., Rohatgi, R. 2025

  Abstract

  The β-catenin destruction complex (BDC) is a central node in WNT/β-catenin signaling, governing embryonic development and adult tissue homeostasis. Although recognized as a prime therapeutic target in colorectal cancer (CRC) for three decades, its dynamic architecture and biochemical complexity have hindered mechanistic understanding. Here, we systematically mapped the sequence-function landscape of the BDC using tiled base editor screens across four endogenous components-CTNNB1, AXIN1, APC, and GSK3B. Validation studies identified ~150 previously unreported mutations across these genes that affected WNT/β-catenin signaling. In addition to known cancer-associated mutations, we discovered rare gain-of-function and separation-of-function alleles of AXIN1 and CTNNB1 that provide mechanistic insights into complex assembly and regulation. We describe a region in β-catenin that regulates its binding to TCF/LEF transcription factors and demonstrate that the AXIN1-β-catenin interface is critical for controlling signaling flux through the oncogenic BDC. Mechanistic studies revealed that assembly of the oncogenic BDC is scaffolded by its own substrate β-catenin, establishing an autoregulatory mechanism that represents an unexploited vulnerability in cancers harboring common APC truncations. Our comprehensive mutational resource provides a foundation for understanding WNT/β-catenin signaling mechanisms in health and disease, while revealing strategies for therapeutic intervention in WNT-driven cancers.

  View details for DOI 10.1101/2025.10.17.683169

  View details for PubMedID 41278994

  View details for PubMedCentralID PMC12633535

• Regulated induced proximity targeting chimeras- RIPTACs-A heterobifunctional small molecule strategy for cancer selective therapies CELL CHEMICAL BIOLOGY Raina, K., Forbes, C. D., Stronk, R., Rappi, J. P., Eastman, K. J., Zaware, N., Yu, X., Bhardwaj, A., Gerritz, S. W., Forgione, M., Hundt, A., King, M. P., Posner, Z. M., Correia, A. D., McGovern, A., Puleo, D. E., Chenard, R., Mousseau, J. J., Vergara, J., Garvin, E., Macaluso, J., Martin, M., Bassoli, K., Jones, K., Garcia, M., Howard, K., Yaggi, M., Smith, L. M., Chen, J. M., Mayfield, A. B., De Leon, C. A., Hines, J., Kayser-Bricker, K. J., Crews, C. M. 2024; 31 (8): 1490-1502.e42

  Abstract

  We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells.

  View details for DOI 10.1016/j.chembiol.2024.07.005

  View details for Web of Science ID 001304314200001

  View details for PubMedID 39116881

  View details for PubMedCentralID PMC11371387