The Cell Adhesion Laboratory

A fundamental question in biology is how cells decide to move, interact, 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. Our laboratory focuses on structure-function studies of cell adhesion in normal and malignant cells.

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. Cell adhesion studies are 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.

We use structural tools (cryogenic electron microscopy, X-ray crystallography, small angle X-ray scattering) as well as biochemistry and cell biology to characterize biological assemblies that comprise cell junctions through the use of structural biology.  

Cell-Cell Junctions

The epithelial, endothelial, and neuronal tissues of multicellular organisms are held together by specialized cell-cell junctions. These are required for several biological processes including wound healing, embryonic morphogenesis, development, differentiation, as well as tissue integrity, homeostasis, and organization. The disassembly of these junctions causes loss of cell polarity and contact inhibition as well as epithelial-to-mesenchymal transitions. Thus, cell-cell junctions need to be regulated dynamically to allow cells to migrate and engage and disengage continuously in adhesive interactions with neighboring cells. Dysregulation of these highly coordinated interactions can lead to the development of cancer and vascular diseases.

Changes in cell-cell adhesion reinitiate cell migration during cell turnover or wound healing or allow metastatic cells to scatter to distant organs. At adhesion complexes, the β-catenin-cadherin receptor complex binds to the cytoskeletal protein α-catenin, which is essential for both the formation and stabilization of cell-cell junctions. Loss of α-catenin or E-cadherin promotes unrestricted growth of cells and facilitates transformation, tumorigenesis, and metastasis. Thus, understanding the molecular mechanisms that control proper assembly and stabilization of these junctions is a fundamental process in cell biology that also goes awry in important pathological scenarios, especially cancer.

Our laboratory collaborates with several other groups and uses structural biology (cryogenic electron microscopy, X-ray crystallography, small angle X-ray scattering) as well as biochemistry and cell biology to determine the dynamic mechanisms of the cell-cell junction to gain insights into diseases, in particular cardiac diseases and cancer where one of our focus is on neurofibromatosis type 2.

Cell-Matrix Junctions

Multicellular organisms have well-defined and tightly regulated mechanisms for cell adhesion where integrin receptors play central roles and regulate processes for normal cell functions such as signaling, cell migration, adhesion to the extracellular matrix (ECM), and leukocyte function. Integrins take part in several biological processes such as development, angiogenesis, immune response, hemostasis, and cancer by regulating cell adhesion. Integrins play key roles in cancer progression and metastasis where certain tumor types exhibit higher levels of certain integrins. Thus, the integrin-associated signaling complex represent an attractive target for cancer therapeutic development.

Several physiological processes require proper control of integrin activation and thus cellular communication with the external environment. Perturbation of these equilibriums may lead to constitutive integrin activation that result in bleeding disorders. Further, inherited defects in ECM proteins result in heritable connective tissue disorders where studies of the interaction of the ECM with the cell via integrins will have an impact. Collectively, understanding the molecular mechanisms that control integrin activation is a fundamental process in cell biology that also goes awry in important pathological statues.

 Our laboratory collaborates with several other groups and uses structural biology (cryogenic electron microscopy, X-ray crystallography, small angle X-ray scattering) as well as biochemistry and cell biology to determine the dynamic mechanisms of the cell-matrix junction to gain insights into diseases, in particular cancer and cardiac diseases.