Control of cell adhesion dynamics by Rap1 signaling

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Individual cells in their particular environments adhere to the extracellular matrix (ECM) and their neighbours via integrin-containing and cadherin-containing complexes, respectively. The dynamics of these interactions regulate the formation and maintenance of complex tissues. An expanding body of evidence accentuates the role of the small Rap1 GTPase and its associated signaling network in many of these processes. In this review we will discuss more recently revealed roles of Rap1 signaling by primarily focusing on functions of the Rap1 effectors RIAM, KRIT-1/CCM1 and AF-6/Afadin in junctional regulation of the vascular system and in epithelial cells. Furthermore, we will describe novel findings on the Rap activator PDZ-GEF in the regulation of cell–cell adhesion between epithelial cells and within a stem cell niche.

Introduction

Integrin-mediated adhesion to the ECM and cadherin-mediated adhesion between cells within developmental and physiological compartments are dynamically regulated. Consequently, failures in efficient adhesion control can result in pathogenic conditions. Interestingly, signaling through the small Rap1 GTPase has been implicated in both integrin-mediated and cadherin-mediated adhesion events. As a member of the Ras superfamily of small GTPases, Rap1 is subject to a GTP/GDP exchange cycle in which dedicated Rap1-specific guanine nucleotide exchange factors (GEFs) promote the exchange of GDP to GTP, thereby converting Rap1 into an active signaling competent form. The latter in turn triggers spacio-temporally defined effector signaling that can stimulate a variety of cellular events. Rap1 GTPase activating proteins (GAPs), on the contrary, terminate the signal output through Rap1 by enhancing its intrinsic rate of GTP hydrolysis. Several Rap1 GEFs, such as C3G, and members of the Epac, CalDAG-GEF and PDZ-GEF subfamilies have been identified, which have been implicated in the regulation of adhesion complexes [1, 2]. Also, several Rap1 effectors have been ascribed to adhesion complexes [1, 2]. In particular, recent light has been shed on the RIAM, KRIT-1/CCM1 and AF-6 proteins and the molecular machineries they impinge on. In this review we will exemplify these by illustrating them in the experimental model systems that enabled their discovery. These include genetically tractable organisms as well as specifically tailored cell culture systems.

Section snippets

Emerging mechanisms for Rap1 signaling in integrin activation

Rap1 has been implicated in a variety of integrin-mediated ‘inside-out’ signaling events. In particular, Rap1 regulates integrin β1, β2 and β3 subunits to affect both integrin affinity and avidity (clustering) [1]. A recent series of observations has unravelled a Rap1-dependent mechanism that could explain how agonist-induced stimulation of platelets modulates their interaction with extracellular ligands. The details of this mechanism probably will be applicable to a number of cell types. Owing

Diverse roles for Rap1 in the endothelium

Research in different arenas has revealed functions for Rap1 in the endothelium and in cells that interact with it. For example, Rap1 regulates adhesion among endothelial cells and also has functions in lymphoid cells that are involved in transendothelial migration [1, 26]. Tight regulation of angiogenesis and permeability of differentiated blood vessels is essential to the homeostasis of any higher organism. Failures in establishing a normal vasculature, in adjusting its architecture to

Rap1 functions in cell shape determination

Many developmental episodes in embryogenesis and organogenesis rely on the precise orchestration of cell shape changes, among which gastrulation offers often striking examples. To accomplish gastrulation processes, cells need to invaginate, intercalate, elongate or migrate, all of which require AJs to be modelled through changes in their associated proteins, including cytoskeletal components [59, 60]. Specifically, work in Drosophila embryogenesis indicated that Rap1 participates in

Conclusions

Rap1 function is integral to signaling pathways that regulate various aspects of different adhesion systems. Different Rap1 GEFs often operate in both integrin and cadherin-based junctional complexes suggesting still unappreciated cross-talking mechanisms. Through its ability to activate several key effector proteins such as RIAM, KRIT-1/CCM and AF-6/Cno, Rap1 can help assemble adhesion-relevant protein complexes. The functions of individual GEFs and effectors are beginning to be resolved and

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We are grateful for Jim Duffy for help with preparation of the figure. Our work described in this review was supported by NIH grant R01-CA096882 to LVA, and BB is a recipient of an NIH postdoctoral training grant (S T32-CA009176). We apologize to those colleagues whose work we did not discuss here.

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