Limits...
Rac and Rho driving tumor invasion: who's at the wheel?

Symons M, Segall JE - Genome Biol. (2009)

Bottom Line: Genome-wide analysis of regulators of Rho-family small GTPases has identified critical elements that control the morphology and invasive behavior of melanoma cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, NY 11030, USA. msymons@nshs.edu

ABSTRACT
Genome-wide analysis of regulators of Rho-family small GTPases has identified critical elements that control the morphology and invasive behavior of melanoma cells.

Show MeSH

Related in: MedlinePlus

Signaling control of mesenchymal and amoeboid cell phenotypes. The reciprocal inhibitory relationship between Rac and Rho signaling cascades establishes a bistable switch that controls the mesenchymal and amoeboid phenotypes. Mesenchymal morphology is controlled by a pathway that activates Rac1 via the adaptor protein NEDD9 and the Rac-specific GEF DOCK3. Rac1 activation results in actin polymerization mediated by the actin-nucleation protein WAVE2, which promotes cell elongation. WAVE2 somehow also suppresses actomyosin contractility and, consequently, amoeboid behavior. On the other hand, Rho/ROCK activation stimulates actomysoin contractility, thereby promoting the amoeboid phenotype, and inhibits Rac by activating the Rac-specific GAP, ARHGAP22. Presumably both Rac1 and Rho activation are ultimately controlled by integrin activity, but precisely how the extracellular environment favors either Rac or Rho signaling remains to be resolved. Solid arrows, direct connections; dashed arrows, indirect connections.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2690992&req=5

Figure 2: Signaling control of mesenchymal and amoeboid cell phenotypes. The reciprocal inhibitory relationship between Rac and Rho signaling cascades establishes a bistable switch that controls the mesenchymal and amoeboid phenotypes. Mesenchymal morphology is controlled by a pathway that activates Rac1 via the adaptor protein NEDD9 and the Rac-specific GEF DOCK3. Rac1 activation results in actin polymerization mediated by the actin-nucleation protein WAVE2, which promotes cell elongation. WAVE2 somehow also suppresses actomyosin contractility and, consequently, amoeboid behavior. On the other hand, Rho/ROCK activation stimulates actomysoin contractility, thereby promoting the amoeboid phenotype, and inhibits Rac by activating the Rac-specific GAP, ARHGAP22. Presumably both Rac1 and Rho activation are ultimately controlled by integrin activity, but precisely how the extracellular environment favors either Rac or Rho signaling remains to be resolved. Solid arrows, direct connections; dashed arrows, indirect connections.

Mentions: Sanz-Moreno et al. also identified WAVE2, a protein that promotes actin nucleation downstream of Rac, as a critical mediator of the elongated phenotype. Interestingly, depletion of either Rac1 or WAVE2 stimulated actomyosin contractility, evidenced by increased phosphorylation of the regulatory subunit of myosin II. This indicates that Rac, through WAVE2, could promote mesenchymal behavior in a dual fashion - by stimulating actin polymerization and cell protrusion and by restraining myosin contractility (Figure 2). Precisely how WAVE2 negatively regulates contractility remains to be defined. Activated Rac has also been shown to stimulate the activity of p190RhoGAP (which downregulates the activity of Rho isoforms), either by directly binding to it and relieving autoinhibition [18] or by promoting its phosphorylation by tyrosine kinases [19]. This suggests there may be additional mechanisms by which Rac can inhibit the Rho-mediated amoeboid phenotype.


Rac and Rho driving tumor invasion: who's at the wheel?

Symons M, Segall JE - Genome Biol. (2009)

Signaling control of mesenchymal and amoeboid cell phenotypes. The reciprocal inhibitory relationship between Rac and Rho signaling cascades establishes a bistable switch that controls the mesenchymal and amoeboid phenotypes. Mesenchymal morphology is controlled by a pathway that activates Rac1 via the adaptor protein NEDD9 and the Rac-specific GEF DOCK3. Rac1 activation results in actin polymerization mediated by the actin-nucleation protein WAVE2, which promotes cell elongation. WAVE2 somehow also suppresses actomyosin contractility and, consequently, amoeboid behavior. On the other hand, Rho/ROCK activation stimulates actomysoin contractility, thereby promoting the amoeboid phenotype, and inhibits Rac by activating the Rac-specific GAP, ARHGAP22. Presumably both Rac1 and Rho activation are ultimately controlled by integrin activity, but precisely how the extracellular environment favors either Rac or Rho signaling remains to be resolved. Solid arrows, direct connections; dashed arrows, indirect connections.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2690992&req=5

Figure 2: Signaling control of mesenchymal and amoeboid cell phenotypes. The reciprocal inhibitory relationship between Rac and Rho signaling cascades establishes a bistable switch that controls the mesenchymal and amoeboid phenotypes. Mesenchymal morphology is controlled by a pathway that activates Rac1 via the adaptor protein NEDD9 and the Rac-specific GEF DOCK3. Rac1 activation results in actin polymerization mediated by the actin-nucleation protein WAVE2, which promotes cell elongation. WAVE2 somehow also suppresses actomyosin contractility and, consequently, amoeboid behavior. On the other hand, Rho/ROCK activation stimulates actomysoin contractility, thereby promoting the amoeboid phenotype, and inhibits Rac by activating the Rac-specific GAP, ARHGAP22. Presumably both Rac1 and Rho activation are ultimately controlled by integrin activity, but precisely how the extracellular environment favors either Rac or Rho signaling remains to be resolved. Solid arrows, direct connections; dashed arrows, indirect connections.
Mentions: Sanz-Moreno et al. also identified WAVE2, a protein that promotes actin nucleation downstream of Rac, as a critical mediator of the elongated phenotype. Interestingly, depletion of either Rac1 or WAVE2 stimulated actomyosin contractility, evidenced by increased phosphorylation of the regulatory subunit of myosin II. This indicates that Rac, through WAVE2, could promote mesenchymal behavior in a dual fashion - by stimulating actin polymerization and cell protrusion and by restraining myosin contractility (Figure 2). Precisely how WAVE2 negatively regulates contractility remains to be defined. Activated Rac has also been shown to stimulate the activity of p190RhoGAP (which downregulates the activity of Rho isoforms), either by directly binding to it and relieving autoinhibition [18] or by promoting its phosphorylation by tyrosine kinases [19]. This suggests there may be additional mechanisms by which Rac can inhibit the Rho-mediated amoeboid phenotype.

Bottom Line: Genome-wide analysis of regulators of Rho-family small GTPases has identified critical elements that control the morphology and invasive behavior of melanoma cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, NY 11030, USA. msymons@nshs.edu

ABSTRACT
Genome-wide analysis of regulators of Rho-family small GTPases has identified critical elements that control the morphology and invasive behavior of melanoma cells.

Show MeSH
Related in: MedlinePlus