Junctional music that the nucleus hears: cell-cell contact signaling and the modulation of gene activity

Abstract

Cell-cell junctions continue to capture the interest of cell and developmental biologists, with an emerging area being the molecular means by which junctional signals relate to gene activity in the nucleus. Although complexities often arise in determining the direct versus indirect nature of such signal transduction, it is clear that such pathways are essential for the function of tissues and that alterations may contribute to many pathological outcomes. This review assesses a variety of cell-cell junction-to-nuclear signaling pathways, and outlines interesting areas for further study.

Figure 1.

Adherens junction signaling to the nucleus. Proteins binding to the intracellular regions of cadherins include catenins, with β-catenin further associating with α-catenin and perhaps indirectly/dynamically with actin microfilaments. The structurally related p120-catenin subfamily is proposed to modulate cadherin lateral clustering, cadherin endocytosis, and activities of Rho-family GTPases. β-catenin acts in various ways within the nucleus, including as a transcriptional coactivator in conjunction with LEF/TCF, whereas p120-catenin relieves Kaiso-mediated gene repression. Other catenins have also been observed in the nucleus, where they have putative or shared roles in transcriptional regulation. Signaling from the nectin/afadin complex to the nucleus may occur indirectly through Ras or Rho, or more directly through afadin's potential association with chromatin or transcriptional modulators. Some evidence has indicated that receptor tyrosine kinases/growth factor receptors, or the frizzled/LRP complex, modulate signals initiated from the adherens junction and vice versa. Dotted circles highlight select signaling entities where research has been focused over the past decade.

Figure 2.

Desmosome junction signaling to the nucleus. Desmosomes are adhesive plaques containing the transmembrane cadherin superfamily members desmocollin and desmoglein, as well as intracellular binding partners such as plakoglobin (γ-catenin), plakophilins (Pkps), and desmoplakin. A number of desmosomal catenins have been localized to the nucleus although the functional relevance remains to be elucidated. Plakophilin-2, for example, has been found to reside within the PolIII complex and to associate with RPC155 and the transcription factor TFIIIB.

Figure 3.

Gap junction signaling to the nucleus. Gap junctions are nonadhesive channels that allow regulated intercellular transmission of electrical or small molecule signals. Connexin 43, a gap junction structural component, has been observed in the nuclei of certain cells and associated with decreased cell proliferation.

Figure 4.

Tight junction signaling to the nucleus. Displayed are pathways associated with tight junctions and suggested or showed to regulate gene expression. Arrows refer to positive functional interactions that could be because of either indirect positive effects or direct physical interactions. Conversely, lines ending with a “T” are negative functional interactions reflecting indirect effects or direct physical interactions. Although most of the junctional proteins depicted associate with junctional membrane proteins, many of the transmembrane entities relevant to the indicated pathways are not known and therefore not indicated.