Regulation of integrin-mediated adhesion during cell migration

Cox, Elisabeth A.; Huttenlocher, Anna

doi:10.1002/(sici)1097-0029(19981201)43:5<412::aid-jemt7>3.0.co;2-f

Cited by 125 publications

(78 citation statements)

References 75 publications

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“…Our findings suggest that the role of Sema3A in GBM migration/dispersal is complex and perhaps biphasic. There is a biphasic relationship between the adhesive strength and cell motility of cells such that there is optimal adhesion for maximal cell motility (DiMilla et al, 1993;Cox and Huttenlocher, 1998). Similarly, our findings are consistent with an optimal Sema3A concentration for GBM dispersal such that GBM cells are able to release their adhesions efficiently and move away from one another.…”

Section: Discussionsupporting

confidence: 86%

Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

et al. 2009

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Glioblastoma multiforme (GBM) is the most malignant glioma type with diffuse borders due to extensive tumor cell infiltration. Therefore, understanding the mechanism of GBM cell dispersal is critical for developing effective therapies to limit infiltration. We identified neuropilin-1 as a mediator of cancer cell invasion by a functional proteomic screen and showed its role in GBM cells. Neuropilin-1 is a receptor for semaphorin3A (Sema3A), a secreted chemorepellent that facilitates axon guidance during neural development. Although neuropilin-1 expression in GBMs was previously shown, its role as a Sema3A receptor remained elusive. Using fluorophore-assisted light inactivation and RNA interference , we showed that neuropilin-1 is required for GBM cell migration. We also showed that GBM cells secrete Sema3A endogenously, and RNA interferencemediated downregulation of Sema3A inhibits migration and alters cell morphology that is dependent on Rac1 activity. Sema3A depletion also reduces dispersal, which is recovered by supplying Sema3A exogenously. Extracellular application of Sema3A decreases cell-substrate adhesion in a neuropilin-1-dependent manner. Using immunohistochemistry, we showed that Sema3A is overexpressed in a subset of human GBMs compared with the non-neoplastic brain. Together, these findings implicate Sema3A as an autocrine signal for neuropilin-1 to promote GBM dispersal by modulating substrate adhesion and suggest that targeting Sema3A-neuropilin-1 signaling may limit GBM infiltration.

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Section: Discussionsupporting

confidence: 86%

Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

et al. 2009

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“…In fibroblasts, calpain inhibition limits migration rates by impairing cell detachment. The differential regulation of integrin at the rear of migrating fibroblasts and neutrophils may account for this discrepancy (30). The primary fate of integrin at the rear of migrating fibroblasts is a severing of the link between integrin and the cytoskeleton, with integrin footprints remaining behind on the substratum as a cell migrates (31,32).…”

Section: Discussionmentioning

confidence: 99%

Calpain regulates neutrophil chemotaxis

Lokuta

Nuzzi

Huttenlocher

2003

Proc. Natl. Acad. Sci. U.S.A.

127

133

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Cell polarization is required for directed cell migration. We investigated the role of the calcium-dependent protease calpain during neutrophil chemotaxis and found that calpain inhibition induced neutrophil adhesion, polarization, and rapid chemokinesis in the absence of exogenous activators. Resting neutrophils display constitutive calpain activity with -calpain being the predominant active isoform. Our findings suggest that constitutive calpain activity in resting neutrophils may function as a negative regulator of protrusion and migration. Specific inhibition of -calpain, but not m-calpain, induced neutrophil polarization and chemokinesis. In contrast to IL-8-induced chemokinesis, the chemokinesis induced by calpain inhibition was not reduced in the presence of pertussis toxin, suggesting that calpain functions downstream of G proteincoupled receptors. Further, both calpain inhibition and stimulation with IL-8 and formyl-Met-Leu-Phe (fMLP) induced an increase in Cdc42 and Rac activation. These findings are consistent with the involvement of calpain in chemotaxis pathways. Accordingly, calpain inhibition decreased neutrophil chemotaxis and directional persistence in a gradient of IL-8 and fMLP. Together, these data reveal a previously uncharacterized function for calpain in neutrophils and suggest that localized modulation of calpain activity may regulate neutrophil chemotaxis downstream of G-protein-coupled receptors. migration N eutrophils, key participants in the innate immune system, are the first responders to inflammatory stimuli such as bacterial infection or tissue injury. This rapid response is achieved by the detection of chemotactic gradients and the polarization and migration of neutrophils toward inflammatory mediators such as formyl-Met-Leu-Phe (fMLP) and IL-8. In the resting state, neutrophils are poorly adherent and exist in a spherical shape. A rapid change in cell morphology occurs in response to inflammatory stimuli such that neutrophils become polarized and migrate toward the inflammatory mediator. The mechanisms that regulate these changes in response to chemoattractants remain poorly understood.There has been recent progress in understanding how cells migrate directionally in a chemoattractant gradient. Although an even distribution of G protein-coupled chemoattractant receptors (GPCRs) has been found on the surface of cells during chemotaxis (1, 2), recent studies have demonstrated that a gradient of chemoattractant can induce an asymmetry in the localization of phosphatidylinositol phosphate (PIP 3 ) with enhancement at the leading edge of migrating neutrophil-like HL-60 cells (3), implying that GPCR activation leads to localized changes in membrane organization and recruitment of signaling intermediates. Previous studies have demonstrated that calpain activity is regulated by polyphosphoinositides (4), raising the intriguing possibility that calpain is an essential signaling intermediate downstream of chemoattractant-induced membrane lipid reorganization. In this paper, we explored th...

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“…Third, calpain 2 is required for efficient lamellipodial extension at the leading edge of motile fibroblasts, but it suppresses protrusions elsewhere [140,166,190,199]. How these opposing functions are controlled is unclear at present.…”

Section: Regulation Of Focal Adhesions and Actin By Proteolysismentioning

confidence: 99%

Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective

Pullikuth

Catling

2007

Cellular Signalling

138

107

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Cell migration is critical for many physiological processes and is often misregulated in developmental disorders and pathological conditions including cancer and neurodegeneration. MAPK signaling and the Rho family of proteins are known regulators of cell migration that exert their influence on cellular cytoskeleton during cell adhesion and migration. Here we review data supporting the view that localized ERK signaling mediated through recently identified scaffold proteins may regulate cell migration.

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Regulation of integrin-mediated adhesion during cell migration

Cited by 125 publications

References 75 publications

Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

Calpain regulates neutrophil chemotaxis

Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective

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