Decoding Membrane Identity and Trafficking Fidelity through Lipid Signaling
Intracellular membranes are highly dynamic, constantly reshaping to meet cellular demands for nutrient uptake, recycling, and signal integration. The identity of each vesicle is carefully encoded by combinations of lipids and proteins that define its fate within the trafficking network. At the Schink Lab, we investigate how membrane trafficking systems use phosphoinositide lipids, Rab GTPases, and protein effectors to establish membrane identity, regulate nutrient uptake, and control invasive cell behavior.
Our research bridges molecular cell biology, lipid signaling, cancer progression, and infection biology. We combine advanced imaging, precise genome engineering, phosphoinositide manipulation, and functional genetic screening to dissect how trafficking pathways adapt to metabolic challenges and how failures in these systems contribute to disease.
Phosphoinositides and Membrane Identity Control
At the heart of our research lies the question of how phosphoinositide lipids encode membrane identity. Phosphoinositides function as dynamic molecular signposts, recruiting specific protein effectors that drive vesicle formation, maturation, and sorting.
We study how phosphoinositide transitions orchestrate identity switches during trafficking. Our work has shown that macropinosomes initially carry a secretory-like identity marked by PtdIns4P and Rab8-family GTPases. The class III PI3-kinase VPS34 subsequently generates PtdIns3P, allowing Rab5 recruitment and promoting endosomal maturation. These transitions serve as critical identity checkpoints to ensure that vesicles are correctly sorted or eliminated if unproductive.
Our ongoing work explores how phosphoinositide-binding proteins — such as Phafin2 — integrate lipid signaling with cytoskeletal remodeling to regulate macropinocytosis, recycling, and selective autophagy. These studies form the mechanistic backbone of our lab’s long-standing expertise in phosphoinositide-regulated membrane trafficking.
Nutrient Scavenging through Macropinocytosis
In nutrient-deprived microenvironments, many cancer cells rely on macropinocytosis to capture extracellular proteins as alternative nutrient sources. KRAS-driven pancreatic cancers, for example, depend heavily on this pathway to support growth under metabolic stress.
Using genome-edited cell models and acute optogenetic control of phosphoinositide metabolism, we investigate how macropinosome formation is triggered. Our work revealed that Phafin2 binds both PtdIns3P and PtdIns4P to coordinate actin remodeling, enabling vesicle closure and maturation.
We also explore how nutrient sensing via mTORC1 and mTORC2 pathways links nutrient availability to invasive behavior — a dynamic balance we describe through the “Drink-or-Drive” model.
In parallel, we study selective autophagy as a complementary membrane remodeling process. We identified DFCP1 as an ATPase regulating omegasome constriction, a key step in autophagosome biogenesis during the clearance of protein aggregates and damaged organelles.
Membrane Recycling and Tubular Sorting
After internalization, cargo must be sorted and recycled to maintain cellular organization. We study how tubular recycling domains maintain membrane identity and balance cargo flow.
Our research has shown that Phafin2 recruits the motor adaptor JIP4 to generate tubular extensions from macropinosomes, enabling efficient recycling of membrane components. In parallel, we identified WDFY2 as a lipid-binding protein that localizes to PtdIns3P-enriched tubular membranes with a preference for high membrane curvature, where it interacts with the SNARE VAMP3 to modulate transmembrane cargo sorting. These tubular hubs serve as key control points that integrate phosphoinositide signaling, membrane shape sensing, and trafficking fidelity.
We continue to expand this work through CRISPR-based functional genetic screens that identify novel regulators of membrane recycling and phosphoinositide conversion.
Membrane Trafficking and Cancer Cell Invasion
Membrane trafficking not only supports nutrient uptake but directly regulates invasive behavior. We discovered that loss of WDFY2 alters recycling of matrix metalloproteinases such as MT1-MMP, enhancing extracellular matrix degradation and promoting invasion.
In parallel, we investigate how metabolic adaptation via macropinocytosis rewires invasion programs during tumor progression, linking trafficking flexibility to metastatic potential.
Pathogen Exploitation of Membrane Trafficking
We study how intracellular pathogens exploit trafficking pathways for entry and replication. Viruses such as Ebola and poxviruses, as well as bacteria like Salmonella, hijack macropinocytosis and vesicle identity transitions to establish replicative niches, providing insight into both infection biology and trafficking system vulnerabilities.
How We Work
Our research combines advanced genetic engineering with quantitative cell biology and lipid manipulation:
- Live-cell and super-resolution microscopy, including high resolution light-sheet, SIM, and DNA-PAINT imaging
- CRISPR/Cas9 genome editing for endogenous protein tagging, gene knockouts, and targeted functional studies
- Lentiviral transgenesis to introduce reporters, optogenetic tools, and lipid-binding probes
- CRISPR-based genetic screens to identify novel regulators of phosphoinositide-regulated trafficking and invasion
- Acute optogenetic control of phosphoinositide metabolism for real-time manipulation of lipid signaling during trafficking events
- Micropatterning and mechanobiology to study membrane-cytoskeleton interactions
- High-content imaging pipelines combined with machine learning-based vesicle classification
- 3D invasion models and organoid cultures to replicate tissue-relevant microenvironments
Our Mission
We aim to uncover how phosphoinositides and membrane trafficking systems establish compartment identity, safeguard nutrient acquisition, coordinate invasive behavior, and protect cellular organization — and how their dysregulation drives cancer, infection, and degenerative disease.