Adhesion molecules in the regulation of cell differentiation: Mainly about Wnt

Other examples of signalling through adhesion molecules

Cadherin in the central nervous system

Apart from their roles in the formation and maintenance of neuronal synapses, the cadherins have signalling functions in nerves. These involve neither E-cadherin nor -catenin but instead, N-cadherin and the-protocadherins. Through a pathway that is as yet unresolved, membrane depolarization or NMDA-R activation (see page 55) causes the activation of membrane proteases, among which are ADAM10 and -secretase. ADAM10 removes the extracellular N-terminus of N-cadherin, which is shed into the synaptic cleft, while -secretase cleaves the cytoplasmic C-terminus. The C-terminal fragment binds CBP (CREB binding protein: see page 430) and together they are destined for degradation by the proteasome. In this way N-cadherin disables CPB/CREB-mediated transcription. The C-terminal fragment of -protocadherin translocates to the nucleus, where it appears to have a transcriptional role. In this way cadherins also make a contribution to synaptic plasticity as regulators of transcription.

JAM and the regulation of differentiation

The abutment of the junctional adhesion molecule JAM with JAM on a neighbouring membrane initiates a series of events that contribute to the organization of polarized epithelial cells (see Figure 14.16). JAM recruits PARs 3 and 6 which in turn attract the GTPase Cdc42 causing activation of the atypical PKC (see page 585). This sets about a process that contributes to junctional assembly and inhibition of proliferation. More surprising, the structural component ZO-1, which binds to occludin, claudin, and JAM, also interacts with the transcription factor ZONAB, required for controlled proliferation rates.111 Sequestration of ZONAB at the tight junction disables transcriptional activity, and cyclin D is amongst the genes that are no longer expressed. In addition, at the membrane ZONAB attracts CDK4 and, in so doing, halts the cell cycle in G1.112

Occludin interacts with the TGF type I receptor

In the presence of TGF 1, its receptor (TGF RI or T RI) binds occludin, a major component of the tight junction. This interaction plays a role in the depolarization of epithelial cells during the epithelial to mesenchymal transition. Epithelial cells expressing an occludin that lacks the second (C-terminal) loop, retain their tight junctions upon addition of TGF 1. This effect is entirely independent of Smad signalling113 (normally linked to T RI signalling, see page 600). Thus occludin recruits the activated TGF type-I

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Signal Transduction

FIG 14.16  Components of the tight junction control junctional organization and cell proliferation. Opposing JAMs initiate a series of

events that result in the organization of the tight junction and arrest of cell proliferation. For details see text.

receptor to the tight junction and this determines their efficient dispersal during the epithelial to mesenchymal transition.

Occludin prevents Raf-1-mediated cell transformation

Transformation of epithelial cells with a constitutively active mutant of Raf-1 is associated with transcriptional down-regulation of occludin. Introduction of exogenous occludin into Raf-1 transformed cells rescues the epithelial phenotype and induces reassembly of functional tight junctions. Moreover, these cells also regain anchorage-dependent growth, indicating that occludin does more than merely restore cell–cell association.114

list of abbreviations

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