Limits...
srGAP1 regulates lamellipodial dynamics and cell migratory behavior by modulating Rac1 activity.

Yamazaki D, Itoh T, Miki H, Takenawa T - Mol. Biol. Cell (2013)

Bottom Line: When both GTPases are activated, the protrusive structures caused by Rac1-dependent actin reorganization are spatially restricted and periodically destabilized, causing ruffling by RhoA-induced actomyosin contractility.Depletion of srGAP1 overactivates Rac1 and inactivates RhoA, resulting in continuous spatiotemporal spreading of lamellipodia and a modal shift of intrinsic cell motility from random to directionally persistent.Thus srGAP1 is a key determinant of lamellipodial dynamics and cell migratory behavior.

View Article: PubMed Central - PubMed

Affiliation: Division of Membrane Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan Laboratory of Lipid Biochemistry, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.

ABSTRACT
The distinct levels of Rac activity differentially regulate the pattern of intrinsic cell migration. However, it remains unknown how Rac activity is modulated and how the level of Rac activity controls cell migratory behavior. Here we show that Slit-Robo GAP 1 (srGAP1) is a modulator of Rac activity in locomotive cells. srGAP1 possesses a GAP activity specific to Rac1 and is recruited to lamellipodia in a Rac1-dependent manner. srGAP1 limits Rac1 activity and allows concomitant activation of Rac1 and RhoA, which are mutually inhibitory. When both GTPases are activated, the protrusive structures caused by Rac1-dependent actin reorganization are spatially restricted and periodically destabilized, causing ruffling by RhoA-induced actomyosin contractility. Depletion of srGAP1 overactivates Rac1 and inactivates RhoA, resulting in continuous spatiotemporal spreading of lamellipodia and a modal shift of intrinsic cell motility from random to directionally persistent. Thus srGAP1 is a key determinant of lamellipodial dynamics and cell migratory behavior.

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Summary. (A) The level of Rac1 activity controls the membrane protrusions. (B) Limitation of Rac1 activity by srGAP1 allows concomitant activation of Rac1 and RhoA at the membrane protrusions.
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Figure 10: Summary. (A) The level of Rac1 activity controls the membrane protrusions. (B) Limitation of Rac1 activity by srGAP1 allows concomitant activation of Rac1 and RhoA at the membrane protrusions.

Mentions: Overactivation of Rac1 causes development of continuous lamellipodial protrusions around the cell, whereas suppression of Rac1 activity inhibits their formation (Pankov et al., 2005). Cell migration is severely repressed in both cases, and thus spatiotemporal activation of Rac1 must be tightly regulated. However, it remains unknown how the level of Rac activity is modulated at lamellipodial protrusions. In this study, we showed that srGAP1 inhibits excessive increase in Rac1 activity at lamellipodia via its RacGAP activity (Figure 10A). srGAP1 is recruited to the lamellipodia in a Rac1-dependent manner, and therefore Rac1 and srGAP1 constitute a negative feedback loop that can limit the maximum intensity of Rac1 signaling (Brandman and Meyer, 2008). Depletion of srGAP1 spatially propagates Rac1 activity throughout the cells, and the structure of cell–substrate adhesions at the lamellipodia is larger in srGAP1-depleted than control cells (Supplemental Figure S9). The positive feedback between increased cell–substrate adhesion and Rac1 activation (Nayal et al., 2006) implies that development of adhesive structures might induce propagation of activated Rac1 throughout the cell in srGAP1-depleted cells.


srGAP1 regulates lamellipodial dynamics and cell migratory behavior by modulating Rac1 activity.

Yamazaki D, Itoh T, Miki H, Takenawa T - Mol. Biol. Cell (2013)

Summary. (A) The level of Rac1 activity controls the membrane protrusions. (B) Limitation of Rac1 activity by srGAP1 allows concomitant activation of Rac1 and RhoA at the membrane protrusions.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3814155&req=5

Figure 10: Summary. (A) The level of Rac1 activity controls the membrane protrusions. (B) Limitation of Rac1 activity by srGAP1 allows concomitant activation of Rac1 and RhoA at the membrane protrusions.
Mentions: Overactivation of Rac1 causes development of continuous lamellipodial protrusions around the cell, whereas suppression of Rac1 activity inhibits their formation (Pankov et al., 2005). Cell migration is severely repressed in both cases, and thus spatiotemporal activation of Rac1 must be tightly regulated. However, it remains unknown how the level of Rac activity is modulated at lamellipodial protrusions. In this study, we showed that srGAP1 inhibits excessive increase in Rac1 activity at lamellipodia via its RacGAP activity (Figure 10A). srGAP1 is recruited to the lamellipodia in a Rac1-dependent manner, and therefore Rac1 and srGAP1 constitute a negative feedback loop that can limit the maximum intensity of Rac1 signaling (Brandman and Meyer, 2008). Depletion of srGAP1 spatially propagates Rac1 activity throughout the cells, and the structure of cell–substrate adhesions at the lamellipodia is larger in srGAP1-depleted than control cells (Supplemental Figure S9). The positive feedback between increased cell–substrate adhesion and Rac1 activation (Nayal et al., 2006) implies that development of adhesive structures might induce propagation of activated Rac1 throughout the cell in srGAP1-depleted cells.

Bottom Line: When both GTPases are activated, the protrusive structures caused by Rac1-dependent actin reorganization are spatially restricted and periodically destabilized, causing ruffling by RhoA-induced actomyosin contractility.Depletion of srGAP1 overactivates Rac1 and inactivates RhoA, resulting in continuous spatiotemporal spreading of lamellipodia and a modal shift of intrinsic cell motility from random to directionally persistent.Thus srGAP1 is a key determinant of lamellipodial dynamics and cell migratory behavior.

View Article: PubMed Central - PubMed

Affiliation: Division of Membrane Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan Laboratory of Lipid Biochemistry, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.

ABSTRACT
The distinct levels of Rac activity differentially regulate the pattern of intrinsic cell migration. However, it remains unknown how Rac activity is modulated and how the level of Rac activity controls cell migratory behavior. Here we show that Slit-Robo GAP 1 (srGAP1) is a modulator of Rac activity in locomotive cells. srGAP1 possesses a GAP activity specific to Rac1 and is recruited to lamellipodia in a Rac1-dependent manner. srGAP1 limits Rac1 activity and allows concomitant activation of Rac1 and RhoA, which are mutually inhibitory. When both GTPases are activated, the protrusive structures caused by Rac1-dependent actin reorganization are spatially restricted and periodically destabilized, causing ruffling by RhoA-induced actomyosin contractility. Depletion of srGAP1 overactivates Rac1 and inactivates RhoA, resulting in continuous spatiotemporal spreading of lamellipodia and a modal shift of intrinsic cell motility from random to directionally persistent. Thus srGAP1 is a key determinant of lamellipodial dynamics and cell migratory behavior.

Show MeSH
Related in: MedlinePlus