Research:

The development and maintenance of multicellular organisms rely on essential processes such as cell division, migration, and differentiation. These fundamental activities are orchestrated by cellular signaling networks that communicate and coordinate cell behavior. Disruptions in these signaling pathways can lead to severe outcomes, including tumor formation and developmental disorders.

Our lab investigates the molecular machinery that ensures accurate signal transmission in both space and time, focusing on the canonical extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway. This pathway plays a central role in embryonic development and cancer progression. While kinases and phosphatases in the pathway have been extensively studied and targeted therapeutically, the mechanisms that control signal specificity and direct diverse biological outcomes remain poorly understood.

A major class of regulators within this pathway are scaffold proteins, which organize signaling complexes and localize them to specific cellular compartments. Our goal is to uncover how scaffold proteins shape ERK1/2 signaling dynamics and contribute to disease.

Research Areas:

1. Mechanisms of signaling specificity and scaffold function

We study how scaffold proteins such as Shoc2 coordinate the assembly and activity of ERK1/2 signaling complexes. Our research explores how Shoc2 and its interacting partners within the ubiquitin-proteasomal system and endocytic trafficking machinery regulate signal fidelity and timing. This NIGMS-funded project combines biochemical, genetic, and imaging approaches to dissect the dynamics and regulation of these signaling complexes.

2. Shoc2 in human development and disease

Genetic variants in SHOC2 cause Noonan-like syndrome with loose anagen hair (NSLH), a developmental disorder belonging to the RASopathy family. We investigate how pathogenic variants alter Shoc2 function and disrupt ERK1/2 signaling. Using zebrafish models and CRISPR-based genome editing, we replicate patient-specific mutations to study their effects on development and disease mechanisms. This work is supported by NICHD.

3. New directions: USP7 and Hao-Fountain syndrome

Building on our expertise in ERK1/2 signaling, we have identified potential links between this pathway and Hao-Fountain syndrome, a neurodevelopmental disorder caused by mutations in the deubiquitinase USP7. Our ongoing NICHD-funded studies aim to uncover how USP7-dependent signaling dysregulation contributes to disease pathogenesis.

Approach and Impact:

We integrate quantitative single-cell microscopy, genetic manipulation, and biochemical analysis in both mammalian cells and zebrafish to achieve a detailed, spatiotemporal understanding of signaling regulation.

Ultimately, our research aims to reveal fundamental principles of signal transduction and contribute to the development of novel, low-toxicity therapies for developmental disorders and cancer.