scholarly journals Quantitative elucidation of a distinct spatial gradient-sensing mechanism in fibroblasts

2005 ◽  
Vol 171 (5) ◽  
pp. 883-892 ◽  
Author(s):  
Ian C. Schneider ◽  
Jason M. Haugh
Keyword(s):  
Signal Amplification ◽  
Total Internal Reflection ◽  
Feedback Loops ◽  
Platelet Derived Growth Factor ◽  
Spatial Gradient ◽  
Gradient Sensing ◽  
Fibroblast Migration ◽  
Phosphoinositide 3 Kinase ◽  
Kinase Pathway ◽  
Amoeboid Cells

Migration of eukaryotic cells toward a chemoattractant often relies on their ability to distinguish receptor-mediated signaling at different subcellular locations, a phenomenon known as spatial sensing. A prominent example that is seen during wound healing is fibroblast migration in platelet-derived growth factor (PDGF) gradients. As in the well-characterized chemotactic cells Dictyostelium discoideum and neutrophils, signaling to the cytoskeleton via the phosphoinositide 3-kinase pathway in fibroblasts is spatially polarized by a PDGF gradient; however, the sensitivity of this process and how it is regulated are unknown. Through a quantitative analysis of mathematical models and live cell total internal reflection fluorescence microscopy experiments, we demonstrate that PDGF detection is governed by mechanisms that are fundamentally different from those in D. discoideum and neutrophils. Robust PDGF sensing requires steeper gradients and a much narrower range of absolute chemoattractant concentration, which is consistent with a simpler system lacking the feedback loops that yield signal amplification and adaptation in amoeboid cells.

scholarly journals F-actin bundles direct the initiation and orientation of lamellipodia through adhesion-based signaling

2015 ◽  
Vol 208 (4) ◽  
pp. 443-455 ◽  
Author(s):  
Heath E. Johnson ◽  
Samantha J. King ◽  
Sreeja B. Asokan ◽  
Jeremy D. Rotty ◽  
James E. Bear ◽  
...  
Keyword(s):  
Focal Adhesion ◽  
Total Internal Reflection ◽  
Cell Shape ◽  
Platelet Derived Growth Factor ◽  
Pi3k Signaling ◽  
Actin Bundles ◽  
Signaling Dynamics ◽  
Ratiometric Imaging ◽  
Phosphoinositide 3 Kinase

Mesenchymal cells such as fibroblasts are weakly polarized and reorient directionality by a lamellipodial branching mechanism that is stabilized by phosphoinositide 3-kinase (PI3K) signaling. However, the mechanisms by which new lamellipodia are initiated and directed are unknown. Using total internal reflection fluorescence microscopy to monitor cytoskeletal and signaling dynamics in migrating cells, we show that peripheral F-actin bundles/filopodia containing fascin-1 serve as templates for formation and orientation of lamellipodia. Accordingly, modulation of fascin-1 expression tunes cell shape, quantified as the number of morphological extensions. Ratiometric imaging reveals that F-actin bundles/filopodia play both structural and signaling roles, as they prime the activation of PI3K signaling mediated by integrins and focal adhesion kinase. Depletion of fascin-1 ablated fibroblast haptotaxis on fibronectin but not platelet-derived growth factor chemotaxis. Based on these findings, we conceptualize haptotactic sensing as an exploration, with F-actin bundles directing and lamellipodia propagating the process and with signaling mediated by adhesions playing the role of integrator.

scholarly journals Postnatal tendon growth and remodeling require platelet-derived growth factor receptor signaling

2018 ◽  
Vol 314 (4) ◽  
pp. C389-C403 ◽  
Author(s):  
Kristoffer B. Sugg ◽  
James F. Markworth ◽  
Nathaniel P. Disser ◽  
Andrew M. Rizzi ◽  
Jeffrey R. Talarek ◽  
...  
Keyword(s):  
Growth Factor ◽  
Biological Activities ◽  
Growth Factor Receptor ◽  
Normal Growth ◽  
Platelet Derived Growth Factor ◽  
Growth And Remodeling ◽  
Fibroblast Migration ◽  
And Migration ◽  
Phosphoinositide 3 Kinase

Platelet-derived growth factor receptor (PDGFR) signaling plays an important role in the fundamental biological activities of many cells that compose musculoskeletal tissues. However, little is known about the role of PDGFR signaling during tendon growth and remodeling in adult animals. Using the hindlimb synergist ablation model of tendon growth, our objectives were to determine the role of PDGFR signaling in the adaptation of tendons subjected to a mechanical growth stimulus, as well as to investigate the biological mechanisms behind this response. We demonstrate that both PDGFRs, PDGFRα and PDGFRβ, are expressed in tendon fibroblasts and that the inhibition of PDGFR signaling suppresses the normal growth of tendon tissue in response to mechanical growth cues due to defects in fibroblast proliferation and migration. We also identify membrane type-1 matrix metalloproteinase (MT1-MMP) as an essential proteinase for the migration of tendon fibroblasts through their extracellular matrix. Furthermore, we report that MT1-MMP translation is regulated by phosphoinositide 3-kinase/Akt signaling, while ERK1/2 controls posttranslational trafficking of MT1-MMP to the plasma membrane of tendon fibroblasts. Taken together, these findings demonstrate that PDGFR signaling is necessary for postnatal tendon growth and remodeling and that MT1-MMP is a critical mediator of tendon fibroblast migration and a potential target for the treatment of tendon injuries and diseases.

scholarly journals Non-genomic action of resveratrol on androgen and oestrogen receptors in prostate cancer: modulation of the phosphoinositide 3-kinase pathway

2007 ◽  
Vol 96 (10) ◽  
pp. 1595-1604 ◽  
Author(s):  
D A Benitez ◽  
E Pozo-Guisado ◽  
M Clementi ◽  
E Castellón ◽  
P M Fernandez-Salguero
Keyword(s):  
Prostate Cancer ◽  
Oestrogen Receptors ◽  
Phosphoinositide 3 Kinase ◽  
Kinase Pathway
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