Alpha2beta1 integrin in cancer development and chemoresistance

Naci, Dalila; Vuori, Kristiina; Aoudjit, Fawzi

doi:10.1016/j.semcancer.2015.08.004

Cited by 94 publications

(89 citation statements)

References 172 publications

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“…42 Similarly, selective inhibition of Grp94 resulted in the degradation of integrin α 2 (Figure 7A,B). Integrin α 2 forms a heterodimer with integrin β 1 on the cell surface, 38 which is responsible for binding to collagen in the extracellular matrix to promote metastasis and invasion. 40 and 48 both induced the degradation of integrin α 2, providing evidence that the decrease in cell migration results from Grp94-selective inhibition.…”

Section: Grp94-selective Inhibition In Cancermentioning

confidence: 99%

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

et al. 2016

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Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum resident of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones. Grp94 associates with many proteins involved in cell adhesion and signaling, including integrins, Toll-like receptors, immunoglobulins, and mutant myocilin. Grp94 has been implicated as a target for several therapeutic areas including glaucoma, cancer metastasis, and multiple myeloma. While 85% identical to other Hsp90 isoforms, the N-terminal ATP-binding site of Grp94 possesses a unique hydrophobic pocket that was used to design isoform-selective inhibitors. Incorporation of a cis-amide bioisostere into the radamide scaffold led to development of the original Grp94-selective inhibitor, BnIm. Structure–activity relationship studies have now been performed on the aryl side chain of BnIm, which resulted in improved analogues that exhibit better potency and selectivity for Grp94. These analogues also manifest superior antimigratory activity in a metastasis model as well as enhanced mutant myocilin degradation in a glaucoma model compared to BnIm.

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Section: Grp94-selective Inhibition In Cancermentioning

confidence: 99%

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

et al. 2016

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“…Integrins are cell adhesion molecules, which are involved in a broad range of cell functions, such as proliferation, differentiation, adhesion, and migration. Defect or dysfunction of integrins, in particular of α2β1 integrin, a prominent collagen binding receptor of many cell types [3] and the only collagen binding integrin on platelets [4], may affect vascular development and angiogenesis [5], epithelial cell differentiation [6], wound repair and fibrosis [7], inflammation [8,9], and cancer and cancer therapy [10], as well as collagen-induced platelet activation, hemostasis, and thrombosis [4,11]. Therefore, α2β1 integrin has become a prominent target in drug research [12–14].…”

Section: Introductionmentioning

confidence: 99%

Dramatic and concerted conformational changes enable rhodocetin to block α2β1 integrin selectively

et al. 2017

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The collagen binding integrin α2β1 plays a crucial role in hemostasis, fibrosis, and cancer progression amongst others. It is specifically inhibited by rhodocetin (RC), a C-type lectin-related protein (CLRP) found in Malayan pit viper (Calloselasma rhodostoma) venom. The structure of RC alone reveals a heterotetramer arranged as an αβ and γδ subunit in a cruciform shape. RC specifically binds to the collagen binding A-domain of the integrin α2 subunit, thereby blocking collagen-induced platelet aggregation. However, until now, the molecular basis for this interaction has remained unclear. Here, we present the molecular structure of the RCγδ-α2A complex solved to 3.0 Å resolution. Our findings show that RC undergoes a dramatic structural reorganization upon binding to α2β1 integrin. Besides the release of the nonbinding RCαβ tandem, the RCγ subunit interacts with loop 2 of the α2A domain as result of a dramatic conformational change. The RCδ subunit contacts the integrin α2A domain in the “closed” conformation through its helix C. Combined with epitope-mapped antibodies, conformationally locked α2A domain mutants, point mutations within the α2A loop 2, and chemical modifications of the purified toxin protein, this molecular structure of RCγδ-α2A complex explains the inhibitory mechanism and specificity of RC for α2β1 integrin.

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“…Several studies that have been performed with 2D models of cell migration have shown the importance of p38 pathway in cell motility. However, p38 has also been associated with cell migration in 3D collagen as is the case with endothelial cells [Hang et al, 2013] and with the invasion of carcinoma cells [Rider et al, 2013;Naci et al, 2015]. Given the more physiological relevance of 3D models of cell migration and the role of p38 in Th17 migration (this study) and in the development of inflammatory diseases, it is likely that p38 might be of critical importance for in vivo T cell migration.…”

Section: Discussionmentioning

confidence: 73%

Human Th17 Migration in Three-Dimensional Collagen Involves p38 MAPK

et al. 2017

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T cell migration across extracellular matrix (ECM) is an important step of the adaptive immune response but is also involved in the development of inflammatory autoimmune diseases. Currently, the molecular mechanisms regulating the motility of effector T cells in ECM are not fully understood. Activation of p38 MAPK has been implicated in T cell activation and is critical to the development of immune and inflammatory responses. In this study, we examined the implication of p38 MAPK in regulating the migration of human Th17 cells through collagen. Using specific inhibitor and siRNA, we found that p38 is necessary for human Th17 migration in three-dimensional (3D) collagen and that 3D collagen increases p38 phosphorylation. We also provide evidence that the collagen receptor, discoidin domain receptor 1 (DDR1), which promotes Th17 migration in 3D collagen, is involved in p38 activation. Together, our findings suggest that targeting DDR1/p38 MAPK pathway could be beneficial for the treatment of Th17-mediated inflammatory diseases. J. Cell. Biochem. 118: 2819-2827, 2017. © 2017 Wiley Periodicals, Inc.

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Alpha2beta1 integrin in cancer development and chemoresistance

Cited by 94 publications

References 172 publications

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

Dramatic and concerted conformational changes enable rhodocetin to block α2β1 integrin selectively

Human Th17 Migration in Three-Dimensional Collagen Involves p38 MAPK

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