Transforming growth factor beta-1 (TGF-beta) acts as both a tumour suppressor and a tumour promoter in a context-dependent manner. The tumour-promoting activities of TGF-beta are likely to result from a combination of Smad and non-Smad signalling pathways but remain poorly understood. Here we show that TGF-beta-mediated activation of RhoA is dependent on the kinase activity of ALK5 and that continuous ALK5 activity maintains basal RhoA-ROCK signalling, cell morphology and actin dynamics in serum-starved rodent fibroblasts independently of Smad2, Smad3 and Smad4. In immortalized human diploid fibroblasts, we show that oncogenic rewiring by transduction of (V12)HaRas instigates regulation of RhoA-ROCK signalling through an autocrine TGF-beta1-ALK5 pathway. Furthermore, we show that ALK5-mediated activation of RhoA is required for efficient (V12)HaRas, V-Raf and (V600E)BRAF transformation and (V12)HaRas-mediated anchorage-independent growth. These findings identify a new pro-oncogenic activity of TGF-beta and indicate that tumours harbouring (V12)HaRas and (V600E)BRAF mutations may be susceptible to TGF-beta signalling inhibitors.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1038/onc.2008.449 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Identification of (PDZ-RhoGEF) as an in vivo regulator of synapses and cognition.
Proc Natl Acad Sci U S A
January 2025
Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706.
Given the influence of cognitive abilities on life outcomes, there is inherent value in identifying genes involved in controlling learning and memory. Further, cognitive dysfunction is a core feature of many neuropsychiatric disorders. Here, we use a combinatory in silico approach to identify human gene targets that will have an especially high likelihood of individually and directly impacting cognition.
View Article and Find Full Text PDFCD271 regulates osteogenic differentiation of ectomesenchymal stem cells via the RhoA/ROCK signaling pathway.
Int Immunopharmacol
January 2025
School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, China. Electronic address:
The low-affinity neurotrophic receptor CD271 plays a crucial role in the osteogenic differentiation of ectomesenchyme stem cells (EMSCs), which is essential for the development and regeneration of jaw bones. This study aimed to investigate the influence of CD271 on EMSCs osteogenic differentiation and to uncover the underlying mechanisms. CD271-deficient mice exhibited delayed mandibular bone development, with a significantly reduction in the expression of osteogenic makers such as ALP, Col-1, OPN, and RUNX2.
View Article and Find Full Text PDFCells under high confinement form highly polarized hydrostatic pressure-driven, stable leader blebs that enable efficient migration in low adhesion, environments. Here we investigated the basis of the polarized bleb morphology of metastatic melanoma cells migrating in non-adhesive confinement. Using high-resolution time-lapse imaging and specific molecular perturbations, we found that EGF signaling via PI3K stabilizes and maintains a polarized leader bleb.
View Article and Find Full Text PDFCigarette smoke extract induces p38-mediated expression and ROS/rho-mediated translocation of alpha 2C adrenoceptor in human microvascular smooth muscle cells.
Prog Cardiovasc Dis
January 2025
Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar. Electronic address:
Raynaud's phenomenon (RP) is a vascular disease characterized by exaggerated vasoconstriction in response to stressors, mainly cold and emotional stress. This vasoconstriction is mediated solely by alpha 2C-adrenoceptors (α-AR) expressed in vascular smooth muscle cells of dermal arterioles. Several factors, among which is cigarette smoking, are associated with aggravated symptoms of and increased risk for RP.
View Article and Find Full Text PDFGradients in cell density and shape transitions drive collective cell migration into confining environments.
Soft Matter
January 2025
Department of Mechanical Engineering & Materials Science, Washington University, St. Louis, USA.
Epithelial cell collectives migrate through tissue interfaces and crevices to orchestrate development processes, tumor invasion, and wound healing. Naturally, the traversal of cell collective through confining environments involves crowding due to narrowing spaces, which seems tenuous given the conventional inverse relationship between cell density and migration. However, the physical transitions required to overcome such epithelial densification for migration across confinements remain unclear.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!