Why Study Cell Adhesion?
The cell is the fundamental unit of life. An essential property of multicellular organisms is their ability to interact with each other. During evolution, organisms co-opted molecules called cadherins, which first appeared in primitive form in single celled choanoflagellates (perhaps functioning to capture prey) to form assemblies called intercellular adherens junctions. Adherens junctions organize and regulate the cortical actin cytoskeleton, mediating morphogenetic movements at sites of cell-cell adhesion in developing tissues and organs. Later, in vertebrates, cadherins evolved further and a new kind of junction appeared called desmosomes (Figure 1). These complex protein assemblies anchor the intermediate filament cytoskeleton to the cell membrane and provide mechanical integrity to tissues, particular those under stress, such as skin and heart. These junctions and associated cytoskeletal filaments are essential for normal morphogenetic movements that occur during embryogenesis and organ homoeostasis and when compromised are involved in tissue remodeling processes that occur in cancer and other diseases.
We now know that these junctions are not simply structural in nature, nor are their functions limited to adhesion. For instance, cadherins also engage in bi-directional signaling with growth factor receptors and their downstream signaling effectors. On one hand, activated growth factor receptor tyrosine kinases (RTKs) can negatively regulate cadherin function during the acquisition of cell motility in tumor invasion, while on the other hand, cadherins both positively and negatively regulate the activity of RTKs. They can also regulate, and even serve as, transducers of mechanical signaling pathways that control cell behavior. And they play a critical role in coordinating the assembly and function of other intercellular junctions, such as tight junctions and gap (communicating junctions), which work together to mediate the multiple functions of cell adhesion and communication required in multicellular organisms. Thus, our laboratory is interested not only in how cadherins and their associated proteins regulate intercellular adhesion, but also how they engage other cell signaling pathways and integrate cytoarchitecture to regulate cell behavior and tissue morphogenesis. The following sections provide some examples of what we do in the Green lab to address these questions.
Gap junctions, are channels made up of connexins that link the cytoplasm of two cells together for the exchange of ions, second messengers, and small metabolites. Epithelial adhesive junctions include Adherens junctions, Desmosomes and Tight junctions. Tight junctions, characterized by the expression of claudins, are restricted to the granular layer of the epidermis and are responsible for forming an epithelial barrier, restricting the paracellular passage of ions and solutes. The cadherin based junctions, Adherens Junctions and Desmsosomes occupy the lateral membranes between neighboring cells in the tissue and are important for maintaining tissue integrity and for regulating cell signaling processes necessary for proper skin development and homeostasis. Adherens junctions contain the classical cadherins, such as E-cadherin, and though cytoplasmic binding partners link the cell membrane to the actin cytoskeleton. Desmosomes are made up of two cadherin families: the desmogleins (Dsg1-4) and desmocollins (Dsc 1-3), which are expressed in a differentiation dependent manner shown to be important for epidermal morphogenesis. The cytoplasmic tails of these cadherins bind to cytoplasmic proteins that are members of the armadillo family, plakoglobin and the plakophilins (1-3), which in turn bind to desmoplakin, a plakin family member and cytolinker between the desmosome and the intermediate filament network.
A Primer on Intercellular Junctions: Nodes at the Intersection of Chemical and Mechanical Signaling
Desmosomes (Figure 3) and related adherens junctions are sites at the plasma membrane between adjacent cells where mechanical and chemical signaling pathways converge. Each type of intercellular junction anchors its own distinct type of cytoskeletal network to the membrane. Desmosomes anchor intermediate filaments to the desmosomal cadherins, desmogleins and desmocollins, through a series of adapter proteins whereas adherens junctions anchor microfilaments to cadherins. In addition to providing tissues with mechanical strength and integrity, these intercellular junctions have also been recognized as sensors that respond to environmental and cellular cues by modulating their assembly state and signaling functions. Adherens junctions and desmosomes are positioned along the basolateral membrane of polarized epithelia, and surround the keratinocytes that make up stratified tissues such as the epidermis and oral cavity. These junctions are also present, along with gap junctions, in the intercalated discs of cardiac myocytes, where they function coordinately to mechanically and electrically couple cells in the heart.