title: Beyond steric hindrance: the role of adhesion signaling pathways in the pathogenesis of pemphigus.
abstract: Epidermal cell adhesion depends on the intercellular interactions of transmembrane cadherin glycoproteins, which form the basis of adherens junctions and desmosomes. Pemphigus is a blistering disease of the skin and mucous membranes characterized by autoantibodies against the cell surface desmosomal cadherins, desmoglein (Dsg) 3 and Dsg1. An unanswered question in pemphigus pathophysiology is the mechanism of acantholysis, or loss of keratinocyte cell adhesion. One longstanding theory for pemphigus pathogenesis is the concept of steric hindrance, in which pathogenic pemphigus autoantibodies cause loss of intercellular adhesion by directly interfering with desmosomal cadherin trans-interactions. However, several recent studies have demonstrated that modulation of p38MAPK, Rho family GTPase, c-myc, protein kinase C, and phospholipase C signaling pathways prevents keratinocyte dissociation induced by pemphigus autoantibodies. As it is unlikely that desmosomal signaling would occur only in response to pemphigus autoantibodies, these studies suggest that numerous different signaling molecules may play a role in desmosomal homeostasis. Many of these same signaling pathways regulate classical cadherins in adherens junctions. Given the recent discovery of bidirectional crosstalk between adherens junctions and desmosomes, it would be valuable to understand how signaling pathways implicated in pemphigus pathogenesis may be involved in more general mechanisms of desmosome and adherens junction regulation. In this review, we will summarize the evidence supporting a role for steric hindrance and signaling mechanisms in the pathogenesis of pemphigus acantholysis and discuss potential analogues in the classical cadherin literature.
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Preety
authors.initials: P
authors.lastname: Sharma
authors.forename: Xuming
authors.initials: X
authors.lastname: Mao
authors.forename: Aimee S
authors.initials: AS
authors.lastname: Payne
mesh_terms: D022005:Adherens Junctions / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D003896:Desmosomes / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D010392:Pemphigus / Q000209:etiology / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*