Klymkowsky Lab research interests - soon to be updated (hopefully)

A key step in the evolution of multicellularity was the coordination between cell adhesion and cell behavior. To generate multicellular organisms, individual cells need to know who they are connected to and who they are, or better put, how they should behave.

Cell behavior has many aspects, but we focus on three: the regulation of cell-cell adhesion, the regulation of cell shape and motility, and the regulatory of gene expression (or is that four?).

Cell shape and motility are based on cytoskeletal systems - microtubules, microfilaments and intermediate filaments and their associated proteins.

These cytoskeletal systems, particularly microfilaments and intermediate filaments are intimately associated with cell adhesion, since they are anchored, regulated by and regulate sites of cell-cell adhesion, adherens junctions and desmosomes.

There are a number of molecularly distinct adhesion systems. One of the most phylogenic ancient are the cadherin-based adherens junctions.
The first evidence for the emergence of a cadherin-based adhesive system appears within the slime molds and the choanoflagellates.

Cadherins are single pass transmembrane proteins that interact with cadherins, generally of the same type on adjacent cells extracellularly, and with catenins intracellularly.

There are a number of different types of cadherins. The first to be identified, uvomorulin is now known as E-cadherin, is characteristic of epithelial cells. Other cadherins are found in other cell types.

More and more cadherins and cadherin-related proteins have been identified in recent years.

We have been primarily concerned with classical and desmosomal cadherins in our work.

Classical cadherins bind to one another in a homotypic (like-binding to like) manner through their extracellular domains.

They interact with the cell's actin filament system via linking proteins known as catenins. Catenins bind to the cadherins cytoplasmic domain.

There are two distinct catenin binding sites. A membrane proximal site interacts with p120^ctn while a more distal region interaction with ß-catenin or plakoglobin (-catenin).

Both ß-catenin and plakoglobin bind -catenin, which in turn binds to actin filaments. This system acts to organize both cell-cell contacts and the actin cytoskeleton.

Desmosomes are the second major class of cadherin-based cell adhesion junctions in vertebrates.

Desmosomes are particularly prominent in the cells of tissues that are under high levels of mechanical stress, e.g. skin and heart.

Desmosomes are based on two distinct types of cadherins, desmogleins and desmocollins, and plakoglobin.

Plakoglobin binds preferentially to the cytoplasmic tails of desmosomal cadherins

Plakoglobin and ß-catenin are clearly evolutionary paralogs. The duplication event that gave rise to plakoglobin appears to be associated with the appearance of the vertebrate lineage.

In contrast to the ß-catenin's of vertebrates, which have changed relatively little over the last 420 million years, plakoglobins have been evolving rapidly -- an indication of greater functional flexibility.

Both ß-catenin and plakoglobin share a common structure, a domain of 12 structural repeats.

It is through this repeat region that ß-catenin and plakoglobin interact with other proteins.

In addition to the C-terminal domain of classical cadherins, this region can also be a transcription factors and regulatory polypeptides (more later).

It is the binding of plakoglobin to desmosomal cadherins that regulates its interactions with the cytoskeleton.

When bound to classical cadherins, both ß-catenin and plakoglobin can bind to -catenin, and so interact with actin filaments.

When plakoglobin binds to desmosomal cadherins, its about to bind to -catenin is blocked,