Expression of the Ly6/uPAR-Domain Proteins C4.4A and Haldisin in Non-Invasive and Invasive Skin Lesions

Abstract

C4.4A and Haldisin belong to the Ly6/uPAR/α-neurotoxin protein domain family. They exhibit highly regulated expression profiles in normal epidermis, where they are confined to early (C4.4A) and late (Haldisin) squamous differentiation. We have now explored if dysregulated expressions occur in non-invasive and invasive skin lesions. In non-invasive lesions, their expression signatures were largely maintained as defined by that of normal epidermis. The scenario was, however, markedly different in the progression towards invasive squamous cell carcinomas. In its non-invasive stage (carcinoma in situ), a pronounced attenuation of C4.4A expression was observed, but upon transition to malignant invasive squamous cell carcinomas, the invasive fronts regained high expression of C4.4A. A similar progression was observed for the early stages of benign infiltrating keratoacanthomas. Interestingly, this transition was accompanied by a shift in the predominant association of C4.4A expression with CK1/10 in the normal epidermis to CK5/14 in the invasive lesions. In contrast, Haldisin expression maintained its confinement to the most-differentiated cells and was hardly expressed in the invasive lesions. Because this altered expression of C4.4A was seen in the invasive front of benign (keratoacanthomas) and malignant (squamous cell carcinomas) neoplasms, we propose that this transition of expression is primarily related to the invasive process.

Crystal Structures of Human C4.4A Reveal the Unique Association of Ly6/uPAR/α-neurotoxin Domain

“…TEX101 regulates fertility [24]. C4.4A and Haldisin define stages of squamous epithelial differentiation [25][26][27].…”

Crystal structure of the unoccupied murine urokinase‐type plasminogen activator receptor (uPAR) reveals a tightly packed DII–DIII unit

“…Within this dimer, the three-dimensional structure of the protomer was almost identical to the monomeric a-CT except for a kink at Pro 7 . In future studies, it is going to be interesting to investigate whether the stable LU domain interface in murine uPAR is a general molecular mechanism or whether other proteins with multiple LU domains, such as C4.4A and Haldisin, have found other solutions for their inter-LU domain assembly [75][76][77]. Two disulfide bonds between Cys 3 in one promoter and Cys 20 in the other were formed (Fig.…”

“…With this description, we have gained a more detailed understanding on how the dynamics of a multi-LU domain-containing protein controls its ligand-binding properties. In future studies, it is going to be interesting to investigate whether the stable LU domain interface in murine uPAR is a general molecular mechanism or whether other proteins with multiple LU domains, such as C4.4A and Haldisin, have found other solutions for their inter-LU domain assembly [75][76][77].…”

Expression and crystallographic studies of the D1D2 domains of C4.4A, a homologous protein to the urokinase receptor

“…The high expression of C4.4A in skin keratinocytes is maintained during the re-epithelization of incisional wounds in mice (Hansen et al, 2004) and in tissue-engineered human skin cultures (B. Jacobsen et al, submitted) as well as in chronic human wounds (Rö sel et al, 1998;Hansen et al, 2004). A comprehensive study of invasive skin lesions shows that C4.4A expression is maintained in stratum spinosum during hyperplasia, but more importantly C4.4A expression reappears in deep invasive lesions whether these are malignant or benign (Kriegbaum et al, 2015). Several studies have reported that C4.4A is highly expressed in various solid cancers of, for example, the breast (Miyake et al, 2015), bladder (Smith et al, 2001;Kriegbaum et al, 2016), kidney (Konishi et al, 2010), colon (Paret et al, 2007;Konishi et al, 2010) and oesophagus (Ohtsuka et al, 2013;Hansen et al, 2008).…”

“…Whereas the urokinase receptor (uPAR) has three LU domains, all of which participate in the dynamic assembly of a high-affinity binding site for its primary ligand uPA, C4.4A has only two LU domains and thus resembles its close structural homologue Haldisin, which is an epithelial biomarker in the stratum granulosum (Gå rdsvoll et al, 2013). Circumstantial evidence suggests that C4.4A plays a role in adhesion, migration and invasion similar to that of uPAR (Smith et al, 2001;Thuma et al, 2013;Kriegbaum et al, 2015). However, how C4.4A interacts with its putative ligands to perform its functions and how the two LU domains are arranged remain unknown.…”