L14: Extra reading Flashcards
cadherins importance
Sivasankar and xie et al. (2023)
Cadherin adhesions withstand mechanical stress and orchestrate complex cell movements during morphogenesis and wound healing (1, 2). Cadherins maintain the integrity of epithelial barriers, thereby preventing harmful agents from accessing underlying tissue. Cadherins are also expressed in a variety of leukocytes, including conventional dendritic cells, Langerhans cells, and macrophages (3). Dysregulation of cadherin adhesion results in a loss of contact inhibition and increased cell mobility, a hallmark of numerous cancers and immunodeficiencies (3, 4).
regulation of the cadherin-catenin complex
Nelson (2012)
The structural integrity of the cadherin–catenin complex is positively and negatively regulated by kinases that are often up-regulated during dynamic cell movements in development and in cancer. Three serine residues in the cadherin cytoplasmic domain (Ser684, Ser686 and Ser692) are phosphorylated by the protein kinases CK2 and GSK3β (glycogen synthase kinase 3β), which creates additional interactions with β-catenin resulting in a large increase in the affinity of the interaction (picomolar affinity [11]). In contrast, tyrosine phosphorylation of β-catenin at Tyr489 or Tyr654 disrupts binding to cadherin, and at Tyr142 disrupts binding to α-catenin [18]. Src phosphorylates β-catenin at Tyr654 [19]. Other tyrosine kinases phosphorylate β-catenin at Tyr489 (Abl [20]), Tyr654 {EGFR (epidermal growth factor receptor) [21]} and Tyr142 (Fer [22]) (Figure 1).
desmosomes
Kowalczyk and green (2015)
Desmosomes are specialized and highly ordered membrane domains that mediate cell-cell contact and strong adhesion. Adhesive interactions at the desmosome are coupled to the intermediate filament cytoskeleton. By mediating both cell–cell adhesion and cytoskeletal linkages, desmosomes mechanically integrate cells within tissues and thereby function to resist mechanical stress [1-3]. This essential structural and mechanical function is highlighted by the prominent distribution of desmosomes in tissues that are routinely subjected to physical forces, such as the heart and skin, and the wide range of desmosomal diseases that result from disruption of desmosome function [4-6]. At the ultrastructural level, desmosomes appear as electron dense discs approximately 0.2–0.5 μm in diameter, which assemble into a mirror image arrangement at cell–cell interfaces [1, 7, 8] (Fig. 1). Large bundles of intermediate filaments extend from the nuclear surface and cell interior out toward the plasma membrane, where they attach to desmosomes by interweaving with the cytoplasmic plaque of the adhesive complex. The overall adhesive function of the desmosome is dependent upon the tethering of intermediate filaments to the desmosomal plaque, highlighting the integrated functions of adhesion and cytoskeletal elements. Thus, desmosomes are modular structures comprising adhesion molecules that bolt cells together, cytoskeletal cables that disperse forces, and linking molecules at the cytoplasmic plaque of the desmosome that carry mechanical load from the adhesion molecules to the intermediate filament cytoskeleton.
focal adhesions and cell migration link
Lagerstee and Houtsmuller (2021)
The driving force required for the motility of eukaryotic cells is primarily produced by actin polymerisation and the force on actin filaments generated by connected contractile myosin [1]. Translating the force on actin fibres into cell movement is mainly taken care of by Focal Adhesions (FAs), macromolecular multiprotein assemblies at the end of actin fibres that connect them to the extracellular matrix (ECM) [2] (Figure 1A). The actin fibres linked to FAs are known as stress-fibres, a specialised form of F-actin or filamentous actin associated with contractile myosin II filaments [2] (Figure 1B). They are typically composed of approximately 10 to 30 actin filaments primarily crosslinked by α-actinin [3,4]. Other actin-crosslinking proteins associated with stress fibres include filamin and fascin [5,6]. Force is produced by the ATP-driven movement of the myosin filaments along the polarised actin filaments, which results in contraction of the stress fibre and a pulling force on the FA complex [7]. Traditionally, two types of stress fibres associated with FAs are recognised. Ventral stress fibres are associated with FAs at either end and typically transverse through the whole cell [8,9]. Dorsal stress fibres are linked to FAs on one end, typically near the cell front, then stretch upwards to the nucleus and the dorsal cell surface [8]. Recently, a third type of stress fibres associated with FAs was recognised, the cortical stress fibres, which are connected to FAs at both ends but are thinner and less contractile than ventral stress fibres [7].
