Get a ligand, get a life: integrins, signaling and cell survival

Abstract

Programmed cell death is crucial for the development and maintenance of multicellular organisms. The decision to live, or to die, depends, at the cellular level, upon the cell's interaction with extracellular cues that trigger cell signaling pathways promoting survival or death. The extracellular matrix (ECM) influences the execution of the apoptotic program through the actions of adhesion receptors. Among these, integrins initiate a variety of downstream signaling events in response to ECM ligation. Integrins directly activate survival pathways via the PI 3-kinase and MAPK pathways and act as essential cofactors for their stimulation by growth factors. Conversely,elevated integrin expression in the absence of appropriate ligands, or in the presence of natural or synthetic antagonists, can promote apoptosis under otherwise permissive growth conditions. Integrins thus act in a crucial biosensory role, coordinating survival or death responses as a function of ECM composition. This dual function provides an elegant mechanism through which tissue-remodeling events may regulate cell death or survival in a temporal,ECM-governed manner.

Integrins as a distinct subtype of dependence receptors

“…Rather, cells tend to express integrins that are matched to the ECM ligands present within their local microenvironment. 12 This matched expression of adhesion receptor and ECM ligand is also observed during developmental 13,14 and tissue remodeling events. 15 In these cases, the repertoire of specific integrins expressed on a given cell type is altered to adjust to concurrent changes within the local ECM.…”

Vascular Endothelial-Cadherin Regulates Cytoskeletal Tension, Cell Spreading, and Focal Adhesions by Stimulating RhoA

“…During blood vessel sprouting and migration in angiogenesis, endothelial cells must disassemble and reform their cell-cell and cell-ECM contacts in synchrony to generate appropriate structures. These two adhesion systems each regulate their functional effects through both biochemical and mechanical signals.Changes in integrin binding to ECM not only alter signals that regulate cell proliferation, migration, and survival (Assoian and Schwartz, 2001;Hood and Cheresh, 2002;Stupack and Cheresh, 2002) but also modulate cell mechanics by affecting focal adhesion (FA) maturation, adhesion strength, cytoskeletal contractility, and cell shape (Geiger and Bershadsky, 2002;Juliano, 2002). Likewise, changes in the engagement of vascular endothelial (VE)-cadherin, the principal junctional molecule in endothelial cells (Dejana et al, 1999), alter both biochemical pathways, such as vascular endothelial growth factor (VEGF) and cell survival signaling (Carmeliet et al, 1999), as well as mechanical states by altering cytoskeletal organization and the local transfer of mechanical stress (Shay-Salit et al, 2002).…”

Phagocytosis and remodeling of collagen matrices

“…With fibroblast cellular remodeling having such critical effects on healing and cancer applications, gaining a better understanding of the fibroblastic remodeling response is important. α1β1 and α2β1 integrins are involved in binding to native collagen type I while αvβ3 is activated in response to denatured collagen type I [56,[59][60][61][62]. The α2β1 integrin binds to the GFOGER sequence in native collagen type I and does not bind to denatured collagen type I [60,62,[63][64][65].…”

“…The α2β1 integrin binds to the GFOGER sequence in native collagen type I and does not bind to denatured collagen type I [60,62,[63][64][65]. The αvβ3 integrin binds to denatured collagen type I almost exclusively via matricryptic RGD sequences that are exposed upon denaturation and unwinding of the triple helix [59,61,[66][67][68]. In our continuing studies to elucidate a mechanistic basis for the results observed, α1β1 and α2β1 in response to native collagen, and αvβ3 in response to denatured collagen and RGD-dependent events, initiate the processes involved in the observations reported (unpublished data).…”