Limits...
Quantitative elucidation of a distinct spatial gradient-sensing mechanism in fibroblasts.

Schneider IC, Haugh JM - J. Cell Biol. (2005)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA.

ABSTRACT
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.

Show MeSH

Related in: MedlinePlus

Integration of external and intrinsic biases in PDGF gradient sensing. Cells are depicted at three positions in a PDGF gradient corresponding to low, intermediate, and high midpoint concentrations. Optimal sensing of the external gradient is seen in a narrow range of intermediate concentrations that is sufficient for maximal PI 3-kinase activation at the plasma membrane. Higher concentrations that saturate receptor occupancy have a leveling effect on PI 3-kinase recruitment across the cell. Hot spots of PI 3-kinase signaling are located at the leading edge and other regions of membrane protrusion, imposing an intrinsic, localized bias that depends on the cell's direction of movement. Thus, when a cell is oriented toward the PDGF source (top), signaling in hot spots tends to synergize with the external gradient, whereas the two spatial biases are in conflict when the cell is oriented away from the source (bottom). This suggests a mechanism by which a fibroblast would migrate with even greater speed and/or persistence when its trajectory is properly aligned with the gradient.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2171296&req=5

fig7: Integration of external and intrinsic biases in PDGF gradient sensing. Cells are depicted at three positions in a PDGF gradient corresponding to low, intermediate, and high midpoint concentrations. Optimal sensing of the external gradient is seen in a narrow range of intermediate concentrations that is sufficient for maximal PI 3-kinase activation at the plasma membrane. Higher concentrations that saturate receptor occupancy have a leveling effect on PI 3-kinase recruitment across the cell. Hot spots of PI 3-kinase signaling are located at the leading edge and other regions of membrane protrusion, imposing an intrinsic, localized bias that depends on the cell's direction of movement. Thus, when a cell is oriented toward the PDGF source (top), signaling in hot spots tends to synergize with the external gradient, whereas the two spatial biases are in conflict when the cell is oriented away from the source (bottom). This suggests a mechanism by which a fibroblast would migrate with even greater speed and/or persistence when its trajectory is properly aligned with the gradient.

Mentions: Another wrinkle in the PDGF-sensing mechanism is the influence of 3′ PI hot spots, which we recently characterized in the context of uniform PDGF stimulation (Schneider et al., 2005). Regions of locally enhanced 3′ PI levels have also been observed in chemoattractant-stimulated D. discoideum (Postma et al., 2004) and primary dendritic cells (Arrieumerlou and Meyer, 2005), although there are differences in the kinetics across cell types. In PDGF-stimulated fibroblasts, hot spots exhibit characteristics that are consistent with locally enhanced PI 3-kinase activation and reduced 3′ PI turnover, and it is conceivable that feedback loops upstream of PI 3-kinase are spatially focused in these regions. Their localization in apparent membrane protrusion structures at the leading edges suggests involvement of the cytoskeleton and/or Rho family GTPases and an importance in cell motility. Thus, as illustrated in Fig. 4, the overall asymmetry in PI 3-kinase signaling depends on the morphological polarity of the cell relative to the gradient. A conceptual model emerges in which cells integrate both intrinsic and external spatial biases in order to migrate persistently toward PDGF gradients (Fig. 7).


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

Schneider IC, Haugh JM - J. Cell Biol. (2005)

Integration of external and intrinsic biases in PDGF gradient sensing. Cells are depicted at three positions in a PDGF gradient corresponding to low, intermediate, and high midpoint concentrations. Optimal sensing of the external gradient is seen in a narrow range of intermediate concentrations that is sufficient for maximal PI 3-kinase activation at the plasma membrane. Higher concentrations that saturate receptor occupancy have a leveling effect on PI 3-kinase recruitment across the cell. Hot spots of PI 3-kinase signaling are located at the leading edge and other regions of membrane protrusion, imposing an intrinsic, localized bias that depends on the cell's direction of movement. Thus, when a cell is oriented toward the PDGF source (top), signaling in hot spots tends to synergize with the external gradient, whereas the two spatial biases are in conflict when the cell is oriented away from the source (bottom). This suggests a mechanism by which a fibroblast would migrate with even greater speed and/or persistence when its trajectory is properly aligned with the gradient.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171296&req=5

fig7: Integration of external and intrinsic biases in PDGF gradient sensing. Cells are depicted at three positions in a PDGF gradient corresponding to low, intermediate, and high midpoint concentrations. Optimal sensing of the external gradient is seen in a narrow range of intermediate concentrations that is sufficient for maximal PI 3-kinase activation at the plasma membrane. Higher concentrations that saturate receptor occupancy have a leveling effect on PI 3-kinase recruitment across the cell. Hot spots of PI 3-kinase signaling are located at the leading edge and other regions of membrane protrusion, imposing an intrinsic, localized bias that depends on the cell's direction of movement. Thus, when a cell is oriented toward the PDGF source (top), signaling in hot spots tends to synergize with the external gradient, whereas the two spatial biases are in conflict when the cell is oriented away from the source (bottom). This suggests a mechanism by which a fibroblast would migrate with even greater speed and/or persistence when its trajectory is properly aligned with the gradient.
Mentions: Another wrinkle in the PDGF-sensing mechanism is the influence of 3′ PI hot spots, which we recently characterized in the context of uniform PDGF stimulation (Schneider et al., 2005). Regions of locally enhanced 3′ PI levels have also been observed in chemoattractant-stimulated D. discoideum (Postma et al., 2004) and primary dendritic cells (Arrieumerlou and Meyer, 2005), although there are differences in the kinetics across cell types. In PDGF-stimulated fibroblasts, hot spots exhibit characteristics that are consistent with locally enhanced PI 3-kinase activation and reduced 3′ PI turnover, and it is conceivable that feedback loops upstream of PI 3-kinase are spatially focused in these regions. Their localization in apparent membrane protrusion structures at the leading edges suggests involvement of the cytoskeleton and/or Rho family GTPases and an importance in cell motility. Thus, as illustrated in Fig. 4, the overall asymmetry in PI 3-kinase signaling depends on the morphological polarity of the cell relative to the gradient. A conceptual model emerges in which cells integrate both intrinsic and external spatial biases in order to migrate persistently toward PDGF gradients (Fig. 7).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus