ABSTRACT
Desmosomes are intercellular adhesive junctions that are particularly prominent in tissues experiencing mechanical stress, such as the heart and epidermis. Whereas the related adherens junction links actin to calcium-dependent adhesion molecules known as classical cadherins, desmosomes link intermediate filaments (IF) to the related subfamily of desmosomal cadherins. By tethering these stress-bearing cytoskeletal filaments to the plasma membrane, desmosomes serve as integrators of the IF cytoskeleton throughout a tissue. Recent evidence suggests that IF attachment in turn strengthens desmosomal adhesion. This collaborative arrangement results in formation of a supracellular network, which is critical for imparting mechanical integrity to tissues. Diseases and animal models targeting desmosomal components highlight the importance of desmosomes in development and tissue integrity, while the downregulation of individual protein components in cancer metastasis and wound healing suggests their importance in cell homeostasis. This chapter will provide an update on desmosome composition, function, and regulation, and will also discuss recent work which raises the possibility that desmosome proteins do more than play a structural role in tissues where they reside.
ABSTRACT
Tyrosine phosphorylation of junctional components has been proposed as a mechanism for modulating cell-cell adhesion. Although a correlation exists between the tyrosine phosphorylation of the adherens junction protein beta-catenin and loss of classical cadherin-mediated adhesion, the effects of tyrosine phosphorylation on the function of the adherens junction and desmosome-associated protein plakoglobin is unknown. In the present study, we investigated the effects of epidermal growth factor receptor (EGFR) tyrosine kinase activation on the subcellular distribution of plakoglobin and its association with its junctional binding partners. Long term epidermal growth factor (EGF) treatment of A431 cells revealed a modest decrease in the cytoskeleton-associated pool of plakoglobin (Pg) and a corresponding increase in the cytosolic pool of Pg. After short term EGF treatment, plakoglobin was rapidly phosphorylated, and tyrosine-phosphorylated Pg was distributed predominantly in a membrane-associated Triton X-100-soluble pool, along with a co-precipitating high molecular weight tyrosine-phosphorylated protein identified as desmoglein 2. Analysis of deletion and point mutants defined the primary EGFR-dependent targets as one or more of three C-terminal tyrosine residues. Whereas phosphorylated Pg remained associated with the desmoglein tail after both short and long term EGFR activation, no phosphorylated Pg was found associated with the N-terminal Pg-binding domain (DPNTP) of the intermediate filament-associated protein, desmoplakin. Together these results are consistent with the possibility that EGF-dependent tyrosine phosphorylation of Pg may modulate cell-cell adhesion by compromising the link between desmosomal cadherins and the intermediate filament cytoskeleton.
