Desmosomes as Signaling Hubs in the Regulation of Cell Behavior

Abstract

Desmosomes are intercellular junctions, which preserve tissue integrity during homeostatic and stress conditions. These functions rely on their unique structural properties, which enable them to respond to context-dependent signals and transmit them to change cell behavior. Desmosome composition and size vary depending on tissue specific expression and differentiation state. Their constituent proteins are highly regulated by posttranslational modifications that control their function in the desmosome itself and in addition regulate a multitude of desmosome-independent functions. This review will summarize our current knowledge how signaling pathways that control epithelial shape, polarity and function regulate desmosomes and how desmosomal proteins transduce these signals to modulate cell behavior.

Keywords: EGFR; Hippo signaling; IGF1R; barrier function; desmosomes; differentiation; inflammation; proliferation.

FIGURE 1

Desmosomes as dynamic structures (created with biorender.com). Desmosomes are composed of the desmosomal cadherins desmoglein (DSG) 1-4 and desmocollin (DSC) 1-3, the armadillo family proteins plakoglobin (PG) and plakophilin (PKP) 1-3 and the plakin family protein desmoplakin (DSP) that anchors keratin filaments. Their expression is tightly regulated at transcriptional, posttranscriptional, translational and posttranslational level. Tissue damage, growth factors and mechanical cues affect desmosomes by altering their composition, localization and function. Thus, the dynamic modulation of desmosomes is crucial for cells adapting to a changing environment.

FIGURE 2

Epidermal growth factor receptor (EGFR) signaling as a critical regulator of desmosomes (created with biorender.com). (Upper panel) Modification of desmosomes by EGFR signaling. Binding of EGF family growth factors to their receptors activates the canonical RAS/RAF/MAPK signaling pathway. Several kinases of the pathway can phosphorylate desmosomal cadherins and PKPs, thereby affecting their stability as well as their localization at the cell membrane. At the same time, EGFR signaling alleviates transcription of desmosomal genes and promotes cell cycle gene expression thereby controlling the balance between proliferation, differentiation and cell-cell adhesion. (Lower panel) Impact of desmosomal proteins on EGFR signaling. The desmosomal cadherins DSG1-3 and DSC2 as well as PKP2 co-localize or interact with the EGFR at the cell membrane, thereby either activating or inhibiting RAS/RAF/MAPK signaling. DSC1/3 and PKP3 affect RAS/RAF/MAPK signaling probably without interfering directly with the EGFR.

FIGURE 3

Insulin like growth factor 1 (IGF1) signaling is an important regulator of epidermal homeostasis (created with biorender.com). Binding of IGF1 activates the IGF1R and the downstream PI3K/AKT signaling cascade via the phosphorylation of its components PI3K, AKT, mTOR, and S6K, resulting in increased proliferation and cell cycle progression as well as decreased apoptosis. Activated AKT2 phosphorylates PKP1, which translocates from the cell membrane to the cytoplasm. Phosphorylated cytoplasmic PKP1 is stabilized and protected from degradation via 14-3-3γ binding, resulting in impaired adhesion but increased proliferation, migration and anchorage independent growth. mTOR and S6K regulate binding of translation initiation factors of the eIF4 complex to mRNAs, thereby promoting protein biosynthesis. Phosphorylated PKP1 interacts with this translation initiation complex and stimulates eIF4A activity thereby facilitating unwinding of secondary structures in the 5′-UTR. The increase in protein biosynthesis correlates with increased proliferation and cell growth.

FIGURE 4

Mechanical cues regulate cellular homeostasis via Hippo signaling (created with biorender.com). Cell-cell contacts control the activation of the Hippo signaling cascade via phosphorylation of MST(Hippo)/SAV and LATS/MOB. The phosphorylated downstream targets YAP/TAZ are degraded via ubiquitylation or stabilized in the cytoplasm by 14-3-3-binding, which facilitates YAP/TAZ association with cell-cell contacts including adherens junctions, tight junctions and desmosomes. Mechanical tension activates RhoA via integrin signaling which promotes stress fiber formation. G protein-coupled receptors (GPCRs) can also activate Rho to promote stress fiber assembly. This inhibits LATS leaving YAP/TAZ in an unphosphorylated state. Unphosphorylated YAP/TAZ translocates from the cytoplasm to the nucleus, where it forms a complex with TEAD transcription factors, resulting in increased transcription of TEAD target genes including DSG1, DSC1-3, PKP1/2, PG, and DSP. Thus, mechanical cues control desmosomal gene expression via the Hippo cascade but, in a feedback mechanism, desmosomes modulate mechanosignaling by capturing YAP/TAZ at the plasma membrane, to maintain the balance between proliferation, differentiation, migration, and invasion.

FIGURE 5

Desmosomal proteins regulate inflammatory processes during wound healing (created with biorender.com). Activated PRR signaling through intrinsic or extrinsic insults as well as upon tissue wounding induce signaling cascades affecting the amount and/or the localization of desmosomal proteins and thus cellular cohesion and proliferation. Moreover, through interfering with various signaling pathways including p38MAPK, Wnt, and Hippo signaling, desmosomal proteins are able to modulate inflammatory responses. Since most desmosomal proteins have been described to dampen inflammation, these proteins could be required to locally restrict inflammatory responses and/or ensure the resolution of inflammatory responses required for tissue regeneration.