Trends in Cell Biology
ReviewRegulation of membrane traffic by integrin signaling
Section snippets
Protein sorting and distribution
Precise regulation of the distribution of proteins and signaling activities within a cell is required for all biological processes, ranging from asymmetric division of stem cells to epithelial cell polarity and planar cell polarity within a tissue. The sorting and distribution of proteins requires the integration of several cellular machineries. First, intrinsic protein sorting signals regulate the partitioning of proteins to various lipid compartments. This occurs at three major sites, the
Integrin regulation of plasma membrane order
The lipid bilayer of the plasma membrane is highly asymmetric, and this asymmetrical organization is crucial for cell physiology. The most obvious example is the organization of the plasma membrane of polarized cells into apical and basolateral macrodomains with distinct lipid compositions. Plasma membranes are further subcompartmentalized into lipid rafts, which are dynamic, highly ordered, nanoscale assemblies enriched in sphingolipids, cholesterol and glycosylphosphatidylinositol
Integrin signaling and endocytosis
Lipid rafts function as plasma membrane scaffolds and as regulators of endocytosis. This function has been studied extensively in the context of caveolae, a specialized subtype of lipid rafts. Caveolae are flask-shaped plasma membrane invaginations that are found in almost all mammalian cell types. In addition to their characteristic morphology, caveolae can be identified by the presence of their main structural component, the intramembrane protein caveolin-1 [19]. Several features distinguish
Integrin signaling and exocytosis
Integrins can also control the secretion of soluble and membrane-associated proteins including growth factors such as transforming growth factor β (TGF-β), VEGF and insulin 48, 49, 50, and proteases such as matrix metalloproteinase-2 [51], which represents an additional mechanism for controlling important cellular activities. While mechanistic insights into how integrins control these processes are still largely lacking, mechanisms underlying integrin-mediated targeted delivery of proteins to
Concluding remarks
It has become clear that adhesion signaling exerts part of its effect on cellular behavior through the regulation of membrane traffic. Future studies will reveal the relative importance of this mode of regulation in respect to other mechanisms of integrin signaling, such as the direct activation of signaling pathways. In addition, the exact molecular details of this regulation require further experimental attention. Sufficient evidence exists to conclude that the regulation of endo- and
Acknowledgements
We thank Roy Zent for comments on the manuscript. Work in the Wickström and Fässler laboratories is supported by the Max Planck Society.
References (85)
- et al.
New insights into membrane trafficking and protein sorting
Int. Rev. Cytol.
(2007) Integrins: bidirectional, allosteric signaling machines
Cell
(2002)Lipids as modulators of proteolytic activity of BACE: involvement of cholesterol, glycosphingolipids, and anionic phospholipids in vitro
J. Biol. Chem.
(2005)Ganglioside GD3 enhances adhesion signals and augments malignant properties of melanoma cells by recruiting integrins to glycolipid-enriched microdomains
J. Biol. Chem.
(2010)Ganglioside modulates ligand binding to the epidermal growth factor receptor
J. Invest. Dermatol.
(2001)Caveolin-stabilized membrane domains as multifunctional transport and sorting devices in endocytic membrane traffic
Cell
(2004)Cells respond to mechanical stress by rapid disassembly of caveolae
Cell
(2011)Integrin alpha1beta1 promotes Caveolin-1 dephosphorylation by activating T cell protein tyrosine phosphatase
J. Biol. Chem.
(2010)- et al.
Signaling on the endocytic pathway
Curr. Opin. Cell Biol.
(2007) alphavbeta3 integrin and angiogenesis: a moody integrin in a changing environment
Curr. Opin. Cell Biol.
(2008)
Ubiquitination of alpha 5 beta 1 integrin controls fibroblast migration through lysosomal degradation of fibronectin-integrin complexes
Dev. Cell
Alpha-V-dependent outside-in signaling is required for the regulation of CD44 surface expression, MMP-2 secretion, and cell migration by osteopontin in human melanoma cells
Exp. Cell Res.
Cargo transport: molecular motors navigate a complex cytoskeleton
Curr. Opin. Cell Biol.
Bidirectional transport: matchmaking for motors
Curr. Biol.
Cortical control of microtubule stability and polarization
Curr. Opin. Cell Biol.
Integrin-linked kinase controls microtubule dynamics required for plasma membrane targeting of caveolae
Dev. Cell
A dual role for integrin-linked kinase in platelets: regulating integrin function and alpha-granule secretion
Blood
Microtubule acetylation promotes kinesin-1 binding and transport
Curr. Biol.
CLIP-170-dependent capture of membrane organelles by microtubules initiates minus-end directed transport
Dev. Cell
F11L-mediated inhibition of RhoA-mDia signaling stimulates microtubule dynamics during vaccinia virus infection
Cell Host Microbe
Actin in membrane trafficking
Curr. Opin. Cell Biol.
Role of actin cortex in the subplasmalemmal transport of secretory granules in PC-12 cells
Biophys. J.
Integrin signaling switches the cytoskeletal and exocytic machinery that drives neuritogenesis
Dev. Cell
The exocyst complex in polarized exocytosis
Curr. Opin. Cell Biol.
The ghost in the machine: small GTPases as spatial regulators of exocytosis
Trends Cell Biol.
RalA-exocyst complex regulates integrin-dependent membrane raft exocytosis and growth signaling
Curr. Biol.
p130Cas regulates the activity of AND-34, a novel Ral, Rap1, and R-Ras guanine nucleotide exchange factor
J. Biol. Chem.
Coordinated protein sorting, targeting and distribution in polarized cells
Nat. Rev. Mol. Cell Biol.
Integrin ligands at a glance
J. Cell Sci.
Genetic and cell biological analysis of integrin outside-in signaling
Genes Dev.
The tail of integrins, talin, and kindlins
Science
Cell adhesion: integrating cytoskeletal dynamics and cellular tension
Nat. Rev. Mol. Cell Biol.
Integrins and extracellular matrix in mechanotransduction
Cold Spring Harb. Perspect. Biol.
Genetic analysis of integrin signaling
Cold Spring Harb. Perspect. Biol.
Lipid rafts as a membrane-organizing principle
Science
Integrin-mediated adhesion regulates membrane order
J. Cell Biol.
Hotspots of GPI-anchored proteins and integrin nanoclusters function as nucleation sites for cell adhesion
Proc. Natl. Acad. Sci. U.S.A.
Lipid rafts and signal transduction
Nat. Rev. Mol. Cell Biol.
An Arg-Gly-Asp-directed receptor on the surface of human melanoma cells exists in an divalent cation-dependent functional complex with the disialoganglioside GD2
J. Cell Biol.
Gangliosides and beta1-integrin are required for caveolae and membrane domains
Traffic
The multiple faces of caveolae
Nat. Rev. Mol. Cell Biol.
Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae
Nature
Cited by (53)
Searching for combination therapy by clustering methods: Stimulation of PKC in Golgi apparatus combined with hypericin induced PDT
2020, Photodiagnosis and Photodynamic TherapyDual-targeting of EGFR and Neuropilin-1 attenuates resistance to EGFR-targeted antibody therapy in KRAS-mutant non-small cell lung cancer
2019, Cancer LettersCitation Excerpt :The bivalent engagement of NRP1 by Fc-TPP11 or Ctx-TPP11 efficiently triggered cellular internalization, which also induced the co-internalization of integrin β3 and KRASMUT due to their physical interactions with NRP1 on the cell surface (Figs. 3 and 4). Given that endocytosed NRP1 and integrin β3 are degraded in lysosomes [38,39], the co-internalized KRASMUT was suggested to be degraded in lysosomes. This resulted in the attenuation of NRP1–integrin β3–KRASMUT downstream signaling, eventually sensitizing KRASMUT NSCLCs to cetuximab.
Emerging strategies to disrupt the central TGF-β axis in kidney fibrosis
2019, Translational ResearchCitation Excerpt :For example, in a rat ischemia-reperfusion injury model, specific antibody neutralization of αvβ5 diminished renal damage that correlated with decreased kidney pericyte adhesion, migration, and vascular permeability.66 The diverse interactions of integrins with pro-mitotic, pro-angiogenic, and pro-fibrotic growth factors and their roles in modulating their signaling and endocytosis have been reviewed previously.67,68 Connective tissue growth factor (CTGF), a strongly pro-fibrotic cytokine that is currently being clinically assessed as a target for treatment of lung fibrosis and other indications (Table 1), is a ligand for both α5β1 and αvβ3.64,69
Molecular Sensors of Blood Flow in Endothelial Cells
2017, Trends in Molecular MedicineThe role of integrins in glaucoma
2017, Experimental Eye Research