International Journal of Molecular Sciences Review Roles of Membrane Domains in Integrin-Mediated Cell Adhesion Daniel Lietha 1 and Tina Izard 2,* 1 Cell Signaling and Adhesion Group, Structural and Chemical Biology, Margarita Salas Center for Biological Research (CIB-CSIC), E-28040 Madrid, Spain; [email protected] 2 Cell Adhesion Laboratory, Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, FL 33458, USA * Correspondence: [email protected] Received: 30 June 2020; Accepted: 31 July 2020; Published: 1 August 2020 Abstract: The composition and organization of the plasma membrane play important functional and regulatory roles in integrin signaling, which direct many physiological and pathological processes, such as development, wound healing, immunity, thrombosis, and cancer metastasis. Membranes are comprised of regions that are thick or thin owing to spontaneous partitioning of long-chain saturated lipids from short-chain polyunsaturated lipids into domains defined as ordered and liquid-disorder domains, respectively. Liquid-ordered domains are typically 100 nm in diameter and sometimes referred to as lipid rafts. We posit that integrin β senses membrane thickness and that mechanical force on the membrane regulates integrin activation through membrane thinning. This review examines what we know about the nature and mechanism of the interaction of integrins with the plasma membrane and its effects on regulating integrins and its binding partners. Keywords: adhesion; integrin signaling; liquid-order; liquid-disorder; lipid rafts 1. Introduction Biomembranes are a key component of life, as they allow the formation of compartments to provide conditions required for biochemical reactions, and also provide an interaction platform for a multitude of key cellular processes. The membranes consist of phospholipids, glycolipids, sterols, and proteins, arranged in a lipid bilayer. The bilayer architecture is a consequence of the amphipathic character of its constituents, which in an aqueous environment with polar regions oriented towards the aqueous phase and hydrophobic regions facing each other. The concept of the bilayer was first postulated in 1935 [1] and then replaced with the fluid mosaic model in 1972 [2]. The latter model is in large part still accepted and describes biomembranes as fluid objects where lipids and proteins are in motion and can freely diffuse along the plane of the lipid bilayer. One main adjustment to the fluid mosaic model of biomembranes is the fact that they have a very high protein content [3,4]. This molecular crowding is increasingly described to occur also in soluble states [5] and drives the separation of phases of distinct contents. The non-homogenous distribution of proteins within the membrane is amplified further through interactions on either side of the membrane. Islands with distinct compositions compared to the rest of the fluid mosaic biomembrane are considered membrane microdomains. Lipid rafts, wherein the spontaneous partitioning of long-chain saturated lipids from short-chain polyunsaturated lipids results in thicker liquid-ordered and thinner liquid-disordered domains, respectively [6,7], as noted by Hansen [8], are the best-characterized membrane microdomain. The fact that lipid rafts do not solubilize in nonionic detergents like triton Int. J. Mol. Sci. 2020, 21, 5531; doi:10.3390/ijms21155531 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 5531 2 of 19 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 19 X-100 at 4 ◦C and are thus called detergent-resistant membranes [9–11] makes them especially difficult to study. LipidLipid rafts rafts are are rich rich in in cholesterol cholesterol and and sphingolipids sphingolipids as as well well as as in in a a variety variety of of proteins proteins [11,12], [12,13], includingincluding lipid-linkedlipid-linked proteins proteins such such as glycosylphosphatidylinositol-anchored as glycosylphosphatidylinositol-anchored proteins proteins and signaling and signalingmolecules. molecules. Thus, they Thus, provide they an provide essential an platform essential for platform cell signaling for cell processes signaling [ 10processes] and play [9] important and play importantroles in the roles regulation in the ofregulation cell adhesion of cell to adhesion the extracellular to the extracellular matrix andassociated matrix and cell associated migration cell by migrationproviding aby sca providingffold that concentratesa scaffold that adaptor concentrates and sca ffadaptorolding proteins,and scaffolding as well asproteins, the actin as cytoskeleton, well as the actineffectors, cytoskeleton, kinases, andeffectors, receptors kinases, to trigger and receptors cancer signaling to trigger events cancer [ 14signaling] (Figure events1). By [13] concentrating (Figure 1). Bysignaling concentrating molecules signaling such as molecules the src family such of as non-receptor the src family tyrosine of non-receptor kinases as welltyrosine as the kinases small GTPaseas well asrac1, the lipid small raft GTPase microdomains rac1, lipid regulate raft microdomains the extracellular regulate matrix-mediated the extracellular cell matrix-mediated migration and direct cell migrationsignaling pathwaysand direct of signaling cell division, pathways cell shape, of cell cell division, motility, andcell shape, cell adhesion cell motility, [10,13,15 and–25 cell]. Specifically, adhesion [9,12,14–24].lipid rafts organize Specifically, signaling lipid molecules rafts organize and provide signaling platforms molecules for celland adhesionprovide signaling.platforms for Several cell adhesionstudies show signaling. that integrins Several studies are associated show that with integrins lipid rafts are [ 26associated–28] and with this interaction lipid rafts [25–27] is important and this for interactiontriggering signalingis important cascades for triggering upon cell signaling attachment ca toscades the extracellular upon cell attachment matrix. to the extracellular matrix. FigureFigure 1. SchematicSchematic of of lipid lipid raft organization. Th Thee asymmetric asymmetric plasma plasma membrane membrane contains phospholipids,phospholipids, glycosphingolipids, cholesterol, and protein receptors that are organized organized in the the thicker thicker lipidlipid microdomains. microdomains. These These lipid lipid rafts rafts compartmentaliz compartmentalizee cellular cellular processes processes and and signal signal transduction transduction by by organizingorganizing and concentrating signalingsignaling moleculesmolecules toto more more favorably favorably interact interact with with protein protein receptors receptors as aswell well as easff ectors.effectors. Lipid Lipid rafts rafts float float freely freely in the in plasmathe plasma membrane membrane while while being being packed packed tighter tighter and more and moreordered ordered compared compared to non-raft to non-raft regions. regions. CellCell adhesion adhesion to to the the extracellular extracellular matrix matrix is is medi mediatedated by by the the integrin integrin transmembrane transmembrane receptor, receptor, a heterodimera heterodimer composed composed of of an an αα andand a aβ βsubunit.subunit. Integrins Integrins attach attach to to extracellular extracellular matrix matrix components, components, suchsuch as as collagen collagen or or fibronectin, fibronectin, and and assemble assemble a a large large focal adhesion protein protein complex that that links links the the adhesionadhesion sites sites to to the actin cytoskeleton. When When boun boundd to to the extracellular matrix, integrins transmit signalssignals withinwithin thethe cell cell that that control control cell cell spreading, spreading, retraction, retraction, migration, migration, and proliferation. and proliferation. These signalsThese signalsdrive many drive physiological many physiological and pathological and pathological processes, processes, such as development, such as development, wound healing, wound immunity, healing, immunity,thrombosis, thrombosis, and cancer and metastasis. cancer metastasis. In this review we discuss the role of lipid rafts in integrin-mediated cell adhesion and how lipid rafts can affect integrin structure and signaling. Although the importance of lipid rafts in cell adhesion has long been recognized, the lack of mechanistic insights has prevented a clear view of how lipid rafts are linked to integrin function. Here we focus on recent findings that have helped to 2 Int. J. Mol. Sci. 2020, 21, 5531 3 of 19 In this review we discuss the role of lipid rafts in integrin-mediated cell adhesion and how lipid Int.rafts J. Mol. can Sci. aff ect2020 integrin, 21, x FOR structure PEER REVIEW and signaling. Although the importance of lipid rafts in cell adhesion3 of 19 has long been recognized, the lack of mechanistic insights has prevented a clear view of how lipid postulaterafts are linkeda detailed to integrin mechanistic function. model Here that we can focus explain on recent how lipid findings rafts that selectively have helped include to activated postulate integrina detailed receptors mechanistic and hence model provide that can a pl explainatform how for active lipid raftsintegrin selectively signaling. include activated integrin receptors and hence provide a platform for active integrin signaling. 2. Cytoskeletal Rearrangements 2. Cytoskeletal Rearrangements The F-actin cytoskeleton interacts and controls many structural and functional aspects of the membraneThe