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TSC2 modulates actin cytoskeleton and focal adhesion through TSC1-binding domain and the Rac1 GTPase.

Goncharova E, Goncharov D, Noonan D, Krymskaya VP - J. Cell Biol. (2004)

Bottom Line: Tuberous sclerosis complex (TSC) 1 and TSC2 are thought to be involved in protein translational regulation and cell growth, and loss of their function is a cause of TSC and lymphangioleiomyomatosis (LAM).The down-regulation of TSC1 with TSC1 siRNA in TSC2-/- cells activated Rac1 and induced loss of stress fibers.Our data indicate that TSC1 inhibits Rac1 and TSC2 blocks this activity of TSC1.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

ABSTRACT
Tuberous sclerosis complex (TSC) 1 and TSC2 are thought to be involved in protein translational regulation and cell growth, and loss of their function is a cause of TSC and lymphangioleiomyomatosis (LAM). However, TSC1 also activates Rho and regulates cell adhesion. We found that TSC2 modulates actin dynamics and cell adhesion and the TSC1-binding domain (TSC2-HBD) is essential for this function of TSC2. Expression of TSC2 or TSC2-HBD in TSC2-/- cells promoted Rac1 activation, inhibition of Rho, stress fiber disassembly, and focal adhesion remodeling. The down-regulation of TSC1 with TSC1 siRNA in TSC2-/- cells activated Rac1 and induced loss of stress fibers. Our data indicate that TSC1 inhibits Rac1 and TSC2 blocks this activity of TSC1. Because TSC1 and TSC2 regulate Rho and Rac1, whose activities are interconnected in a reciprocal fashion, loss of either TSC1 or TSC2 function may result in the deregulation of cell motility and adhesion, which are associated with the pathobiology of TSC and LAM.

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Schematic representation of the TSC2-dependent modulation of actin cytoskeleton and focal adhesion. TSC1 inhibits Rac1, and TSC2 blocks this activity of TSC1. TSC2 through its specific TSC1-binding domain forms a complex with TSC1, which is a prerequisite for Rac1 activation and Rho inhibition. This, in turn, promotes stress fiber disassembly and focal adhesion remodeling. Dysregulation of TSC2 function due to inactivating mutations promotes deregulation of the TSC1–TSC2 complex formation, followed by deregulating Rac1 and Rho activation, which, in turn, results in abnormal cell motility and adhesion associated with LAM and TSC pathobiology.
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fig10: Schematic representation of the TSC2-dependent modulation of actin cytoskeleton and focal adhesion. TSC1 inhibits Rac1, and TSC2 blocks this activity of TSC1. TSC2 through its specific TSC1-binding domain forms a complex with TSC1, which is a prerequisite for Rac1 activation and Rho inhibition. This, in turn, promotes stress fiber disassembly and focal adhesion remodeling. Dysregulation of TSC2 function due to inactivating mutations promotes deregulation of the TSC1–TSC2 complex formation, followed by deregulating Rac1 and Rho activation, which, in turn, results in abnormal cell motility and adhesion associated with LAM and TSC pathobiology.

Mentions: TSC1 has been identified as an activator of Rho and a regulator of cell adhesion (Lamb et al., 2000). The Rho-activating domain of TSC1 overlaps with the region that binds TSC2 (Nellist et al., 1999, 2001; Hodges et al., 2001), indicating that TSC2 may modulate TSC1-dependent activation of Rho. Our work identifies a novel function of TSC2 as a modulator of the actin cytoskeleton and focal adhesion remodeling. In our model, TSC1 inhibits Rac1, and TSC2 blocks this activity of TSC1 that is a prerequisite to the activation of Rac1 and the subsequent inhibition of Rho; this, in turn, promotes stress fiber disassembly and focal adhesion remodeling (Fig. 10). Loss of function of either TSC1 or TSC2 due to inactivating mutations potentially promotes deregulation of the TSC1–TSC2 complex formation followed by deregulation of Rac1 and Rho activities, which, consequently, induces abnormal cell motility associated with the pathobiology of LAM and TSC.


TSC2 modulates actin cytoskeleton and focal adhesion through TSC1-binding domain and the Rac1 GTPase.

Goncharova E, Goncharov D, Noonan D, Krymskaya VP - J. Cell Biol. (2004)

Schematic representation of the TSC2-dependent modulation of actin cytoskeleton and focal adhesion. TSC1 inhibits Rac1, and TSC2 blocks this activity of TSC1. TSC2 through its specific TSC1-binding domain forms a complex with TSC1, which is a prerequisite for Rac1 activation and Rho inhibition. This, in turn, promotes stress fiber disassembly and focal adhesion remodeling. Dysregulation of TSC2 function due to inactivating mutations promotes deregulation of the TSC1–TSC2 complex formation, followed by deregulating Rac1 and Rho activation, which, in turn, results in abnormal cell motility and adhesion associated with LAM and TSC pathobiology.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172598&req=5

fig10: Schematic representation of the TSC2-dependent modulation of actin cytoskeleton and focal adhesion. TSC1 inhibits Rac1, and TSC2 blocks this activity of TSC1. TSC2 through its specific TSC1-binding domain forms a complex with TSC1, which is a prerequisite for Rac1 activation and Rho inhibition. This, in turn, promotes stress fiber disassembly and focal adhesion remodeling. Dysregulation of TSC2 function due to inactivating mutations promotes deregulation of the TSC1–TSC2 complex formation, followed by deregulating Rac1 and Rho activation, which, in turn, results in abnormal cell motility and adhesion associated with LAM and TSC pathobiology.
Mentions: TSC1 has been identified as an activator of Rho and a regulator of cell adhesion (Lamb et al., 2000). The Rho-activating domain of TSC1 overlaps with the region that binds TSC2 (Nellist et al., 1999, 2001; Hodges et al., 2001), indicating that TSC2 may modulate TSC1-dependent activation of Rho. Our work identifies a novel function of TSC2 as a modulator of the actin cytoskeleton and focal adhesion remodeling. In our model, TSC1 inhibits Rac1, and TSC2 blocks this activity of TSC1 that is a prerequisite to the activation of Rac1 and the subsequent inhibition of Rho; this, in turn, promotes stress fiber disassembly and focal adhesion remodeling (Fig. 10). Loss of function of either TSC1 or TSC2 due to inactivating mutations potentially promotes deregulation of the TSC1–TSC2 complex formation followed by deregulation of Rac1 and Rho activities, which, consequently, induces abnormal cell motility associated with the pathobiology of LAM and TSC.

Bottom Line: Tuberous sclerosis complex (TSC) 1 and TSC2 are thought to be involved in protein translational regulation and cell growth, and loss of their function is a cause of TSC and lymphangioleiomyomatosis (LAM).The down-regulation of TSC1 with TSC1 siRNA in TSC2-/- cells activated Rac1 and induced loss of stress fibers.Our data indicate that TSC1 inhibits Rac1 and TSC2 blocks this activity of TSC1.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

ABSTRACT
Tuberous sclerosis complex (TSC) 1 and TSC2 are thought to be involved in protein translational regulation and cell growth, and loss of their function is a cause of TSC and lymphangioleiomyomatosis (LAM). However, TSC1 also activates Rho and regulates cell adhesion. We found that TSC2 modulates actin dynamics and cell adhesion and the TSC1-binding domain (TSC2-HBD) is essential for this function of TSC2. Expression of TSC2 or TSC2-HBD in TSC2-/- cells promoted Rac1 activation, inhibition of Rho, stress fiber disassembly, and focal adhesion remodeling. The down-regulation of TSC1 with TSC1 siRNA in TSC2-/- cells activated Rac1 and induced loss of stress fibers. Our data indicate that TSC1 inhibits Rac1 and TSC2 blocks this activity of TSC1. Because TSC1 and TSC2 regulate Rho and Rac1, whose activities are interconnected in a reciprocal fashion, loss of either TSC1 or TSC2 function may result in the deregulation of cell motility and adhesion, which are associated with the pathobiology of TSC and LAM.

Show MeSH
Related in: MedlinePlus