BBA - Molecular Cell Research (v.1692, #2-3)

Preface to cell adhesion and signalling by Rudy L Juliano (vi-vii).

Integrins were so named for their ability to link the extracellular and intracellular skeletons. Now almost 20 years into integrin research, numerous questions remain as to how this interaction is accomplished and how it is modified to achieve a desired phenotype. As the cell adhesion and actin assembly fields are merging in combined approaches, novel actin assembly mechanisms are being uncovered. Some of the earliest identified cytoplasmic linker molecules, believed to mediate integrin-actin binding, are once again the subject of scrutiny as potential dynamic mediators of cell anchorage. It seems plausible that each unique cellular morphology occurs as the result of activation of distinct actin assembly systems that are either stabilized by unique bundling and linker proteins or modified for progression to a new phenotype. While this research initiative is likely to continue rapidly in a forward fashion, it remains to be clarified how integrins assemble the most stable and basic cytoskeletal phenotype, the adherent cell with prominent stress fibers. Recent investigations point towards a shift in the current model of anchoring at the cell periphery by providing both mechanisms and evidence for de novo actin assembly orchestrated by the adhesion site. Lacking a complete pathway from integrin ligation to an integrated extracellular–intracellular skeleton in any single system, this review proposes a simple model of integrin-mediated stress fiber integration by drawing from work in multiple systems.
Keywords: Integrin; Actin; Cell adhesion;

Cell–extracellular matrix (ECM) adhesion is mediated by transmembrane cell adhesion receptors (e.g., integrins) and receptor proximal cytoplasmic proteins. Over the past several years, studies using biochemical, structural, cell biological and genetic approaches have provided important evidence suggesting crucial roles of integrin-linked kinase (ILK), PINCH and CH-ILKBP/actopaxin/affixin/parvin (abbreviated as parvin herein) in ECM control of cell behavior. One general theme emerging from these studies is that the formation of ternary protein complexes consisting of ILK, PINCH and parvin is pivotal to the functions of PINCH, ILK and parvin proteins. In addition, recent studies have begun to uncover the molecular mechanisms underlying the assembly, functions and regulation of the PINCH–ILK–parvin (PIP) complexes. The PIP complexes provide crucial physical linkages between integrins and the actin cytoskeleton and transduce diverse signals from ECM to intracellular effectors. Among the challenges of future studies are to define the functions of different PIP complexes in various cellular processes, identify additional partners of the PIP complexes that regulate and/or mediate the functions of the PIP complexes, and determine the roles of the PIP complexes in the pathogenesis of human diseases involving abnormal cell–ECM adhesion and signaling.
Keywords: PINCH; ILK; Parvin; Cell–extracellular matrix adhesion; Cytoskeleton; Signaling;

The molecular coupling of CAS and Crk in response to integrin activation is an evolutionary conserved signaling module that controls cell proliferation, survival and migration. However, when deregulated, CAS/Crk signaling also contributes to cancer progression and developmental defects in humans. Here we highlight recent advances in our understanding of how CAS/Crk complexes assemble in cells to modulate the actin cytoskeleton, and the molecular mechanisms that regulate this process. We discuss in detail the spatiotemporal dynamics of CAS/Crk assembly and how this scaffold recruits specific effector proteins that couple integrin signaling networks to the migration machinery of cells. We also highlight the importance of CAS/Crk signaling in the dual regulation of cell migration and survival mechanisms that operate in invasive cells during development and pathological conditions associated with cancer metastasis.
Keywords: Crk; Crk-associated substrate; Migration; Integrin; Abl; Tyrosine phosphorylation;

Control of motile and invasive cell phenotypes by focal adhesion kinase by David D Schlaepfer; Satyajit K Mitra; Dusko Ilic (77-102).
Cell motility is stimulated by extracellular stimuli and initiated by intracellular signaling proteins that localize to sites of cell contact with the extracellular matrix termed focal contacts. Focal adhesion kinase (FAK) is an intracellular protein-tyrosine kinase (PTK) that acts to regulate the cycle of focal contact formation and disassembly required for efficient cell movement. FAK is activated by a variety of cell surface receptors and transmits signals to a range of targets. Thus, FAK acts as an integrator of cell motility-associated signaling events. We will review the stimulatory and regulatory mechanisms of FAK activation, the different signaling connections of FAK that are mediated by a growing number of FAK-interacting proteins, and the modulation of FAK function by tyrosine and serine phosphorylation. We will also summarize findings with regard to FAK function in vertebrate and invertebrate development as well as recent insights into the mechanistic role(s) of FAK in promoting cell migration. As increased FAK expression and tyrosine phosphorylation have been correlated with the progression to an invasive cell phenotype, there is growing interest in elucidating the important FAK-related signaling connections promoting invasive tumor cell movement. To this end, we will discuss the effects of FAK inhibition via the dominant-negative expression of the FAK C-terminal domain termed FAK-related non-kinase (FRNK) and how these studies have uncovered a distinct role for FAK in promoting cell invasion that may differ from its role in promoting cell motility.
Keywords: FAK; Src; Motility; Invasion; Tyrosine phosphorylation; Signal transduction;

Focal adhesion regulation of cell behavior by Michele A Wozniak; Katarzyna Modzelewska; Lina Kwong; Patricia J Keely (103-119).
Focal adhesions lie at the convergence of integrin adhesion, signaling and the actin cytoskeleton. Cells modify focal adhesions in response to changes in the molecular composition, two-dimensional (2D) vs. three-dimensional (3D) structure, and physical forces present in their extracellular matrix environment. We consider here how cells use focal adhesions to regulate signaling complexes and integrin function. Furthermore, we examine how this regulation controls complex cellular behaviors in response to matrices of diverse physical and biochemical properties. One event regulated by the physical structure of the ECM is phosphorylation of focal adhesion kinase (FAK) at Y397, which couples FAK to several signaling pathways that regulate cell proliferation, survival, migration, and invasion.
Keywords: Focal adhesion; Focal adhesion kinase; Integrin; src; 3D matrix; Cell migration; Tubulogenesis;

The interaction of cells with surrounding matrix and neighbouring cells governs many aspects of cell behaviour. Aside from transmitting signals from the external environment, adhesion receptors also receive signals from the cell interior. Here we review the interrelationship between adhesion receptors, tyrosine kinases (both growth factor receptor and non-receptor) and modulators of the actin cytoskeletal network. Deregulation of many aspects of these signalling pathways in cancer highlights the need for a better understanding of the complexities involved.
Keywords: Tyrosine kinase; Integrin; Adherens junction; Actin cytoskeleton; Cancer;

Regulation of Bcl-2 proteins during anoikis and amorphosis by Stuart S Martin; Kristiina Vuori (145-157).
Adhesion to extracellular matrix regulates cell survival through both integrin engagement and appropriate cell spreading. Numerous signaling pathways converge to affect the levels and posttranslational modifications of Bcl-2 family proteins. Recent work has defined specific roles for different Bcl-2 proteins in the disruption of mitochondrial function that leads to cell death. Using this understanding of Bcl-2 protein function as a framework, we will consider the molecular mechanisms of apoptosis induced by integrin detachment (anoikis) and cell death stimulated by the loss of cytoskeletal architecture (amorphosis).
Keywords: Integrin; Cytoskeleton; Bcl-2; Apoptosis; Anoikis; Amorphosis;

A wide variety of soluble signaling substances utilize the cyclic AMP-dependent protein kinase (PKA) pathway to regulate cellular behaviors including intermediary metabolism, ion channel conductivity, and transcription. A growing literature suggests that integrin-mediated cell adhesion may also utilize PKA to modulate adhesion-associated events such as actin cytoskeletal dynamics and migration. PKA is dynamically regulated by integrin-mediated cell adhesion to extracellular matrix (ECM). Furthermore, while some hallmarks of cell migration and cytoskeletal organization require PKA activity (e.g. activation of Rac and Cdc42; actin filament assembly), others are inhibited by it (e.g. activation of Rho and PAK; interaction of VASP with the c-Abl tyrosine kinase). Also, cell migration and invasion can be impeded by either inhibition or hyper-activation of PKA. Finally, a number of A-kinase anchoring proteins (AKAPs) serve to associate PKA with various components of the actin cytoskeleton, thereby enhancing and/or specifying cAMP/PKA signaling in those regions. This review discusses the growing literature that supports the hypothesis that PKA plays a central role in cytoskeletal regulation and cell migration.
Keywords: cAMP; PKA; Actin; Cytoskeleton; Cell migration; Cell adhesion;