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First published online April 1, 2009
doi: 10.1242/10.1242/jcs.039446

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Adhesion signaling – crosstalk between integrins, Src and Rho

Division of Toxicology, Leiden Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, 2300 RA Leiden, The Netherlands

View larger version (18K): [in this window] [in a new window]   Fig. 1. The Rho-GTPase activation cycle. Model depicting how Rho-GTPases are regulated. Rho-GDP dissociation inhibitors (Rho-GDIs) sequester inactive GDP-bound Rho-GTPases (Rho) in the cytoplasm. When released from Rho-GDIs, Rho-GTPases are targeted to the plasma membrane, where their activation cycle is regulated by GEFs that promote GTP loading and activation of Rho-GTPases. Inactivation of Rho-GTPases is mediated by GAPs that promote GTP hydrolysis to GDP.

View larger version (17K): [in this window] [in a new window]   Fig. 2. Overview of Rho-GTPases, the GAPs and GEFs that regulate them and the effector pathways that act downstream of integrins. An overview of the currently known GEFs (indicated in blue) and GAPs (indicated in red) that control the activation of RhoA, Rac1 and Cdc42 downstream of integrins is shown. Through the recruitment and activation of different effector proteins (indicated in green) these Rho-GTPases regulate the actin cytoskeletal dynamics that are required for membrane protrusions and/or cytoskeletal contractility. See main text for additional details.

View larger version (82K): [in this window] [in a new window]   Fig. 3. Integrin regulation of Rho-GTPases during early and late stages of cell spreading. (A) During early stages of cell spreading, the FAK-Src complex activates several pathways that lead to protrusive activity via Rac and Cdc42 GTPases at sites of integrin ligation. At the same time, this complex, together with syndecans, mediates suppression of actomyosin contractility by keeping the activity of RhoA low. Broken lines indicate protein-protein interactions. (B) At later stages of cell spreading, integrins stimulate the activity of several GEFs, which leads to a shift in the balance between RhoA and Rac1 activity in favor of RhoA, thereby enhancing RhoA-mediated actomyosin contractility. Integrin 5β1 is particularly efficient at promoting this second phase of cell spreading, which might involve force-induced activation of SFKs. See main text for additional details. Broken arrows indicate transition not supported by presented pathway or not supporting presented output.

View larger version (30K): [in this window] [in a new window]   Fig. 4. Src binding to β3 integrins influences cell spreading via regulation of Rac1 GTP loading. Following ligand binding, IIbβ3 and vβ3 integrins can directly interact with the SH3 domain of Src via the cytoplasmic domain of integrin β3. These interactions result in a release of Csk from tyrosine 530 and induce the activation of Src. Clustering of β3 integrins promotes transphosphorylation in the kinase domain of Src. This is followed by the recruitment and phosphorylation of Syk, which can occur in concert with signaling downstream from growth-factor receptors. Activated Syk phosphorylates Vav proteins, which act as GEFs for Rac1. Alternatively, activated Src can phosphorylate and regulate the activation of the RacGEF Tiam1. In turn, activated Rac1 induces membrane protrusions and spreading. Broken arrows indicate transition not supported by presented pathway or not supporting presented output. See main text for additional details.

View larger version (42K): [in this window] [in a new window]   Fig. 5. Crosstalk between integrins and EGFR regulates Src activation to control Rho-GTPases. Integrins can promote Src-mediated phosphorylation of EGFR in the absence of growth factors, which occurs through a signaling complex that involves Src, p130Cas and Crk. Unengaged but activated EGFR signals through PI3K and Vav2 to promote Rac1 GTP loading. The binding of EGF to EGFR results in the direct activation of Src, which might be enhanced in the presence of integrin–FAK-Src complexes. Src activation then leads to the activation of DIP1, which in turn interacts with p190RhoGAP (leading to the inactivation of RhoA) and with Vav2 (leading to the activation of Rac1). See main text for additional details. Broken arrows indicate transition not supported by presented pathway or not supporting presented output.

View larger version (86K): [in this window] [in a new window]   Fig. 6. The involvement of integrin-SFK crosstalk in physiological processes. The ability of integrins to regulate Rac and Rho GTPases through SFKs controls intracellular processes involved in hemostasis (A), bone resorption (B), bacterial uptake by non-phagocytic cells (C) and leukocyte extravasation (D). A schematic overview of the molecular pathways that are known to occur downstream of integrin engagement in each of these processes is shown. M-CSF, macrophage colony-stimulating factor; CSF1R, colony-stimulating-factor 1 receptor. See main text for additional details. Broken arrows indicate transition not supported by presented pathway or not supporting presented output.

View larger version (29K): [in this window] [in a new window]   Fig. 7. Integrin–SFK–Rho-GTPase crosstalk in directional migration. The balance between the activity of RhoA and Rac1 is regulated differently in the retracting rear (A) and the protrusive front (B) of the cell body. In A, RhoA activity is required to prevent Rac1-stimulated formation of multiple lamellipodia that would interfere with directionality, and supports the high turnover of cell-matrix adhesions observed in the retracting rear of the cell. In B, RhoA-induced contractility is suppressed while Rac1 activity drives the formation of the lamellipodium at the leading edge. Integrins can regulate this spatial segregation of Rho-GTPase activities through the pathways that involve SFKs, GEFs and GAPs as described in the previous figures. See main text for additional details.

View larger version (26K): [in this window] [in a new window]   Fig. 8. Crosstalk in mechanotransduction. Integrins are necessary for translating the mechanical properties of the microenvironment (such as substrate rigidity) into intracellular signaling pathways. This is thought to involve tension-dependent conformational alterations in integrin-associated proteins, such as Src, p130Cas and vinculin, and might involve signaling through Rho-GTPases to remodel the actin cytoskeleton. Conversely, cytoskeletal tension might act on this same protein complex to regulate dynamic integrin-ligand interactions and ECM remodeling. Such mechanotransduction pathways regulate various cellular processes, including differentiation and proliferation. See main text for additional details.

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