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The importance of keeping in touch: regulation of cell-cell contact in the exocrine pancreas
  1. M V Apte,
  2. J S Wilson
  1. Pancreatic Research Group, The University of New South Wales, Sydney, Australia
  1. Correspondence to:
    Associate Professor M Apte
    Director, Pancreatic Research Group, South Western Sydney Clinical School, The University of New South Wales, Level 2, Thomas and Rachel Moore Education Centre, Liverpool Hospital, Liverpool, NSW 2170, Australia; m.apteunsw.edu.au

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New insights into the mechanisms regulating acinar cell-cell contact in the exocrine pancreas, with evidence to support a role for PTPκ as a key molecule in stabilisation of the adhesion complex in acinar cells via continuous dephosphorylation of the cadherin-catenin complex

The formation of tissues and organs of multicellular organisms during embryonic development involves a highly regulated process of integration and segregation of heterogeneous cell populations into organised cell patterns.1 One of the major regulators of the processes of cell migration, proliferation, and differentiation during organogenesis is cell-cell adhesion, which is predominantly mediated by cell surface glycoproteins. These cell adhesion proteins can respond to cell signalling events and can also transduce signals into the cell.2 Four major groups of cell adhesion proteins have been described, including integrins, immunoglobulins, selectins, and cadherins.

Cadherins are a superfamily of integral membrane proteins that are subdivided into six gene families.1 E-cadherin, a member of the classical cadherin type I family, has been widely studied in a variety of epithelial cell systems.2–5 Like most cadherins, E-cadherin is a transmembrane glycoprotein with an extracellular domain that interacts with the extracellular domains of cadherin molecules of adjacent cells in a calcium dependent homophilic manner. The highly conserved intracellular (cytoplasmic) domain of E-cadherin functions as a binding site for catenins (cytoplasmic proteins that anchor E-cadherin to the cell cytoskeleton). Typically, E-cadherin binds to β-catenin or p120 catenin in the cells; these catenins in turn are associated with α-catenin which links the cadherin-catenin complex to the cytoskeletal protein F-actin within the cell. The formation of cadherin-catenin complexes is critical to cell-cell adhesion. Both cadherins and catenins contain phosphorylation sites which regulate their function at intercellular junctions.6 It has now been established that cell adhesion complexes do not function as static structures but are subjected to highly regulated changes during tissue development and/or repair.7

Loss or alteration of cell-cell contact is a feature of many pathological states, including the relatively slow process of tumour invasion and metastasis and the relatively rapid events of inflammation and oedema formation. Regulation of adhesion complexes in tumorigenesis and inflammatory conditions of the skin has been widely studied8,9,10 but little is known about the factors regulating cell-cell contact in a complex epithelial organ such as the pancreas. The functional unit of the exocrine pancreas is the acinus, comprising individual acinar cells arranged around a central lumen.11 Each acinar cell is in close contact with adjacent acinar cells through cell-cell adhesions, including tight junctions (which seal the paracellular routes between adjacent cells), GAP junctions (intercellular channels connecting the cytoplasm of adjacent cells), and adherens junctions (specialised regions of adhesion at the basolateral plasma membrane). Acute inflammation of the pancreas (acute pancreatitis) is characterised by the development of interstitial oedema (associated with loss of contact between acinar cells within the tissue12) and infiltration of inflammatory cells into the parenchyma.

The study by Schnekenburger and colleagues13 in this issue of Gut deals with the regulation of adherens junction integrity in pancreatitis and represents a logical progression of previous work by this group14,15 describing the dissociation, internalisation, and reassembly of the adherens junction during acute experimental pancreatitis (see page 1445). In the current study,13 the authors have endeavoured to identify the mechanisms responsible for adherens junction dissociation in pancreatitis using both in vitro (isolated acini exposed to supramaximal caerulein stimulation) and in vivo (mouse model of mild caerulein induced pancreatitis) approaches. The self limiting nature of pancreatic injury in the caerulein pancreatitis model enabled the authors to study cell adhesion regulation not only during injury but also during the restitution (repair) phase.

Cell-cell contact can potentially be disturbed by alterations in the expression or function of adherens junction proteins and/or by disruptions in the actin cytoskeleton. A number of recent reports in the literature (using cancer cell lines, metastatic fibroblasts, epithelial cells) have described a role for tyrosine phosphorylation of adherens junction proteins in the perturbation of cell-cell contacts.4,16–18 Corollary evidence has been provided by studies demonstrating that a dephosphorylated state of cell adhesion proteins (via the action of protein tyrosine phosphatases (PTPs)) is essential for the maintenance of an intact cell adhesion complex.19,20

Using a number of elegant experimental protocols, Schnekenburger and colleagues13 have been able to describe a time course of the changes occurring in the adhesion complexes of acinar cells during the development (at one hour after caerulein injection) and resorption (at 48 hours after caerulein injection) of oedema in acute pancreatitis. A significant increase in tyrosine phosphorylation of catenins (β-catenin and p120 catenin) and E-cadherin was observed early in the course of injury (at one and two hours after caerulein injection), although expression of the proteins themselves remained unchanged. The increase in tyrosine phosphorylation of β-catenin and E-cadherin coincided with dissociation of the complex from the transmembrane phosphatase PTPκ (known to be constitutively associated with the cadherin-catenin complex in normal cells), redistribution of adhesion proteins from the lateral and apical cell membrane to the cytosol (internalisation), and subsequently, an association of the complex with the cytosolic protein tyrosine phosphatase PTP SHP-1 over 2–4 hours. At 48 hours, resorption of oedema was associated with the reassembly of the adhesion complex and its relocation to the lateral and apical cell membranes. In vitro studies with isolated acini demonstrated that inhibition of PTPs by orthovanadate induced acinar cell dissociation in a manner similar to that observed with supramaximal caerulein, supporting the concept that tyrosine phosphorylation was a key regulator of the cadherin-catenin complex.

Two observations of interest in this study were: (i) the lack of any changes in protein expression of the adhesion complex during caerulein pancreatitis in vivo and (ii) the in vitro finding that disruption of the actin cytoskeleton did not influence cell dissociation. Both of these observations strengthen the concept that pancreatic acinar cell dissociation during caerulein pancreatitis is predominantly regulated by tyrosine phosphorylation and dephosphorylation of the proteins of the adhesion complex, and is independent of any alterations in protein levels or the integrity of the actin cytoskeleton.

This study makes a significant contribution to our understanding of the mechanisms regulating acinar cell-cell contact in the exocrine pancreas, with evidence to support a role for PTPκ as a key molecule in stabilisation of the adhesion complex in acinar cells via continuous dephosphorylation of the cadherin-catenin complex. However, important questions remain with respect to disruption of acinar contact in the pathophysiological setting. Schnekenburger et al13 assert that acinar dissociation in caerulein pancreatitis is observed ultrastructurally before the development of oedema, thereby excluding a “physical” cause (such as increased pressure due to accumulation of fluid in the interstitium) for acinar cell dissociation. If acinar dissociation precedes (and is not the effect of) oedema, it would be logical to ask what factors disrupt the mechanisms regulating cell-cell adhesion in the earliest stages of pancreatitis and what factors stimulate reassembly of disrupted adhesion complexes during the repair phase of the disease. Future studies in this area will no doubt be designed to address these issues by examining: (i) the cellular events during acute pancreatitis which disrupt the constitutive association of PTPκ with the adhesion complex and/or trigger tyrosine phosphorylation of the complex; (ii) whether proteolytic cleavage of E-cadherin during acute necroinflammation plays a role in triggering tyrosine phosphorylation of the adhesion complex leading to cell dissociation and; and (iii) the potential roles of intracellular catenins in restitution of the adhesion complex after internalisation. Elucidation of the above processes has the potential to identify specific molecules/pathways that could be therapeutically targeted to: (i) prevent/inhibit disruption of cell adhesion in the initial phase of acute pancreatitis (thereby maintaining a physical barrier to inhibit inflammatory cell infiltration into the gland) and (ii) stimulate the reassembly of the cell adhesion complex during recovery from the disease.

New insights into the mechanisms regulating acinar cell-cell contact in the exocrine pancreas, with evidence to support a role for PTPκ as a key molecule in stabilisation of the adhesion complex in acinar cells via continuous dephosphorylation of the cadherin-catenin complex

REFERENCES

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Footnotes

  • Conflict of interest: None declared.

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