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The Cell Adhesion Laboratory

The laboratory focuses on structure-function studies of cell adhesion in normal and malignant cells

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A fundamental question in biology is how cells decide to move, contact, grow, differentiate, or die during tissue development. Clearly, metazoans require cell adhesion to keep them together. Adhesion receptors also provide transmembrane connections that link the extracellular matrix and adjacent cells to the intracellular actin cytoskeleton while also serving as signal transducers.

We study the molecular basis and biological consequences of cell adhesion to understand how the engagement of adhesion receptors impacts many aspects of cell behavior including cell shape, polarization, cytoskeletal organization, motility, proliferation, survival, and differentiation. The understanding of cell adhesion is crucial to understand pathological processes since altered adhesion properties are features of cancer cells while tight adhesion regulation is crucial to hemostasis, thrombosis, leukocyte trafficking, and inflammation.

Adhesion complexes that direct contacts of cells with their neighbors or with the extracellular matrix play essential roles in development and in cell growth, survival, morphogenesis, motility, and migration. These diverse responses are directed by pathways that relay signals to regulate transcriptional programs in the nucleus, but also by changes in the actin cytoskeleton and the microtubule network. These ‘backbones’ of the cell function as scaffolds for an array of signaling pathways and enzymatic reactions, and they also undergo dynamic changes in their structure and organization that allow cells to break and form new contacts as they migrate, ruffle their membranes, and to send out filopodia and lamellipodia. Without such controls, cell migration becomes chaotic, growth ceases, and cells die via anoikis.

Inositol phospholipids are crucial regulators of cell physiology and their headgroup interactions play fundamental roles in controlling membrane/cytosol interfaces. In addition to signal transduction at the cell surface, these lipids regulate a range of cellular processes including membrane traffic, polarity, nuclear events, the permeability and transport functions of membranes, and the cytoskeleton. Phosphatidylinositol-4,5-bisphosphate (PIP2) participates in the recruitment and activation of a wide variety of adaptor proteins and actin regulatory proteins at the plasma membrane thus regulating cytokines, cell shape, motility, as well as several other processes. Binding of PIP2 to actin-binding proteins that link the membrane to the actin cytoskeleton is critical for cell-cell or cell-matrix adhesion.

We seek to understand how actin and lipids bind to and alter the functions of the large arrays of proteins that regulate many essential aspects of cell biology, and to provide a platform for targeting such interactions for therapeutic intervention in diseases such as ischemia, myopathies, and metastatic cancer that have involve anomalies in cell adhesion and cell migration.

Specifically, we want to understand how PIP2 directly regulates the actin cytoskeleton by modulating the activity and targeting of actin regulatory proteins, how binding of selected cytoskeletal proteins to membrane lipids promotes clustering, and how PIP2 mediates crosstalk between the actin cytoskeleton and an expanding spectrum of essential functions. These studies will be an essential first step towards the possibilities of devising therapeutic strategies in pathological conditions, including cancer.