Mol Bio Colloquium
Mol Bio Colloquium
- Graduate StudentDevenport Lab
Liu YangPostdoctoral FellowShvartsman Lab
Mol Bio Graduate Colloquium
Investigating the role of epidermal E-cadherin in melanocyte morphology and migration
The skin provides a crucial barrier function that is the first line of defense against mechanical and environmental assaults. This stratified organ consists of a microenvironment of varying cell types that function in unison to support the skin’s role in defending the organism. Namely, the epidermis consists of tightly adherent epithelial cells that are interspersed with immune and pigment producing melanocytes that are essential for the skin’s protective function against infection and UV radiation. Despite their protective function against harmful UV radiation, dysregulation of melanocyte function can cause melanoma, the most lethal form of skin cancer. Although substantial progress has been made in identifying genetic alterations within melanocytes that lead to melanoma, much less is known about how the melanocyte environment contributes to its function. A major goal of this proposal is to define how interactions between melanocytes and the surrounding epithelium supports normal melanocyte function and constraints progression to metastatic melanoma. Thus, my central question is, “How does keratinocyte E-cadherin impact both wild type (WT) and transformed melanocyte morphology and migration”?
Broadcasting ERK activation to the cell
The extracellular signal-regulated kinase (ERK) pathway is vital in organismal development and a common target for anticancer drugs. The impact of aberrant signaling on human diseases occurs at the level of protein phosphorylation, underpinning efforts to identify downstream substrates of ERK. However, a complete picture of the in vivo substrates repertoire is still lacking. In prior studies, perturbations conducted in cell cultures with indirect or slow kinase targeting mechanisms often lead to activation of parallel pathways. Here, we combined acute optogenetic perturbations that toggle the ERK pathway between on and off states with phosphoproteomics of finely staged embryos. We identified 314 candidate ERK substrates with 489 phosphorylation sites, which were involved in diverse biological processes including signaling transduction, transcription regulation, cell cycle regulation, chromosome remodeling, and RNA processing. Switching ERK on or off recovered phosphorylation changes of known substrates in their respective directions and revealed a handful of new candidate phosphosites on Capicua, the early embryo’s primary interpreter of ERK signaling. Our data also reveal additional ERK effectors involved in mitosis process, suggesting an underappreciated role of ERK in cell cycle regulation. Our results pave the way for exploring how ERK may regulate the activity of generalist phosphatases or other kinases in vivo, and how quickly the effects are compounded throughout the phosphoproteome.