The desmosomal plaque proteins of the plakophilin family

Abstract

Three related proteins of the plakophilin family (PKP1_3) have been identified as junctional proteins that are essential for the formation and stabilization of desmosomal cell contacts. Failure of PKP expression can have fatal effects on desmosomal adhesion, leading to abnormal tissue and organ development. Thus, loss of functional PKP 1 in humans leads to ectodermal dysplasia/skin fragility (EDSF) syndrome, a genodermatosis with severe blistering of the epidermis as well as abnormal keratinocytes differentiation. Mutations in the human PKP 2 gene have been linked to severe heart abnormalities that lead to arrhythmogenic right ventricular cardiomyopathy (ARVC). In the past few years it has been shown that junctional adhesion is not the only function of PKPs. These proteins have been implicated in cell signaling, organization of the cytoskeleton, and control of protein biosynthesis under specific cellular circumstances. Clearly, PKPs are more than just cell adhesion proteins. In this paper we will give an overview of our current knowledge on the very distinct roles of plakophilins in the cell.

Figure 1

Immunohistochemical staining of sections of human skin with antibodies against PKP 1. Sections of formaldehyde-fixed tissue samples of human skin were stained with a monoclonal antibody (clone PP1 5C2; Progen, Heidelberg; for methods see [18]) against PKP 1 a to d. (a) Overview of epidermis showing a strong reaction of the antibodies at the desmosomes of all layers. (b) At a higher magnification, the basal layers exhibit a somewhat weaker desmosomal staining that can be resolved occasionally into individual spot-like desmosomes containing PKP 1. During keratinocyte differentiation, desmosomal labeling is getting more pronounced. (c) Cross-section of a hair follicle (Hf) with desmosomal staining of the outer root sheath while the hair-shaft is not stained (Sg, sebaceous gland). Arrow marks the duct of a sebaceous gland. (d) Eccrine sweat ducts are marked intensively by antibodies while the secretory portions of eccrine glands show a distinct but weaker staining (arrow). Apocrine sweat glands (lower left corner) are negative. Scale bars: 100 μm (b); 200 μm a, c, and d.

Figure 2

Position of mutations in human PKP 1 gene. Schematic representation of the protein structure of PKP 1 with head domain “Head” in blue color containing the homologous region 2 “HR2” near the amino-terminus which is followed by nine armadillo repeats (yellow boxes; numbered in circles from 1 to 9). Finally, a short domain (blue) at the carboxyl-terminus is shown. Positions of homozygous mutations are marked by double arrows, positions of compound heterozygous mutations by connected arrows. Green arrows designate mutations affecting the coding region, red arrows denote splice-site mutations. For numbering and references of the mutations see Table 1.

Figure 3

Immunohistochemical staining of sections of human skin a, and b and liver c, and d with antibodies against PKP 2. (a) The staining of samples of human skin with a monoclonal antibody against PKP 2 (clone PP2-150; Progen, Heidelberg) demonstrates a weak and delicate desmosomal staining as well as cytoplasmic staining in the basal layer of the interfollicular epidermis (arrow). Suprabasal keratinocytes remain unstained. (b) Eccrine sweat glands and ducts show a strong reaction with PKP 2-specific antibodies while apocrine sweat glands exhibit an apical, distinct but weak desmosomal reaction (arrow). (c) Hepatocytes as well as bile ductules are marked at the cell-cell contacts by PKP 2-specific antibodies (arrow). (d) Bile ducts also show a sharp and apical staining of desmosomal structure by the PKP 2-antibodies. The samples shown in (c) and (d) are derived from liver tissue in the vicinity of a metastasis of a gastrointestinal stromal tumor with portal and periportal fibrosis and ductal and ductular proliferation. Scale bars: 100 μm (d), 200 μm (a, b, c).

Figure 4

Immunohistochemical staining of sections of human skin a, and b and liver c, and d with antibodies against PKP 3. (a) Intensive reaction of desmosomes and cytoplasm is visible by staining sections of human skin with a monoclonal antibody against PKP 3 (clone PKP3 310.9.1; Progen, Heidelberg). Basal and lower suprabasal keratinocytes exhibit a strong cytoplasmic staining while desmosomal staining is less prominent. With ongoing differentiation, the desmosomal labeling is increasing. (b) Eccrine and apocrine (arrows) sweat glands show strong desmosomal labeling with PKP 3-specific antibodies. (c) Reaction of PKP 3-specific antibodies on liver is restricted to bile ductules (arrow; see description of liver tissue in the legend to Figure 3) while hepatocytes are completely negative for PKP 3. The insert presents a magnification of a bile ductule of human liver stained with antibodies against PKP 3, exhibiting a labeling of the desmosomal junctions. (d) Bile ducts (here in a large portal field) show a clear desmosomal reaction at the apical pole of cells (arrow). Scale bars: 100 μm (d), 200 μm a, b, c.