Research

Cells produce a matrix and their interaction with elements of this matrix has a profound influence on their behavior. The focus of the research in the Jones lab is to understand how matrix molecules, via their interaction with cell surface receptors, regulate a variety of cell behaviors including proliferation, differentiation and migration. We focus on two tissue systems: the skin and the lung.

Skin Research

Over 25 years ago our goal was to identify the components of the hemidesmosome which tethers the skin cells (keratinocytes) in the basal layer of the epidermis to the dermis. During these earlier studies we were among the first to demonstrate that human autoantibodies recognize two distinct hemidesmosome proteins, now termed BPAG1e and collagen type XVII. Moreover, we also showed that the α6β4 integrin nucleates hemidesmosome assembly by binding its extracellular ligand laminin-332 (formerly called laminin-5).

Skin Diagram Edited

More recently, we have uncovered roles for these same molecules during migration of keratinocytes and have defined signaling pathways via which they do so.

Skin Diagram 2

In one of our recent studies we have demonstrated the functional importance of α6 integrin in regulating cell motility (see movies below). α6 integrin-deficient keratinocytes move in an aberrant manner. Moreover, during the course of the studies, we discovered that α6β4 integrin regulates the transcription and translation of several important integrin subunits.

Keratinocyte moving over an uncoated substrate. Images were taken every 2 minutes over a 2 hour period.

Keratinocyte moving over an uncoated substrate.
Images were taken every 2 minutes over a 2 hour period.

There moving keratinocytes lack the hemidesmosomal integrin subunit alpha 6 integrin. These appear to lack the ability to move in a directed fashion and exhibit multiple lamellipodia.

There moving keratinocytes lack the hemidesmosomal integrin subunit alpha 6 integrin. These appear to lack the ability to move in a directed fashion and exhibit multiple lamellipodia.

In two recent publications, we have provided evidence that actinin isoforms differentially impact skin cell migration. Actinin-4 regulates directed migration, while actinin-1 controls the engine of motility.

Lung Studies

Our work in the lung centers on the assembly and function of laminin molecules secreted by the epithelial cells that line the alveolar compartment of the lung. These epithelial cells are involved in oxygen exchange and the production of surfactant proteins. Our published studies reveal that  alveolar epithelial cells assemble laminin-311 into fibers and that these fibers transit mechanical signals in the form of stretch to activate a variety of signaling pathways.  Our current studies center on the role of laminin-311 during ventilator-induced injury in the lung and during the development of fibrosis.

Lung Diagram

Primary alveolar epithelial cells have the unusual ability to form distinct matrix adhesions and display highly novel arrangements of actin. We describe these unique characteristics in a recent paper. An image of a primary alveolar epithelial cell grown on a micro-patterned substrate is shown below.

Primary alveolar epithelial cells are co-stained for actin (red) and vinculin (green). Note the unusual central array of actin and the perinuclear ring of focal contacts stained by the vinculin antibody.

Primary alveolar epithelial cells are co-stained for actin (red) and vinculin (green). Note the unusual central array of actin and the perinuclear ring of focal contacts stained by the vinculin antibody.

Current Projects

  1. How do hemidesmosomal proteins connect to the actin cytoskeleton to regulate lamellipodia formation and directed cell migration?
  2. What are the mechanisms that regulate matrix deposition in keratinocytes?
  3. How do alveolar epithelial cells contribute to wound repair in the lung and what role do integrins play in this process?
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