Letizia Lanzetti | Università degli Studi di Torino (original) (raw)
Uploads
Papers by Letizia Lanzetti
Current Biology, 2013
Background: Integrin-mediated adhesion of cells to the extracellular matrix (ECM) relies on the d... more Background: Integrin-mediated adhesion of cells to the extracellular matrix (ECM) relies on the dynamic formation of focal adhesions (FAs), which are biochemical and mechanosensitive platforms composed of a large variety of cytosolic and transmembrane proteins. During migration, there is a constant turnover of ECM contacts that initially form as nascent adhesions at the leading edge, mature into FAs as actomyosin tension builds up, and are then disassembled at the cell rear, thus allowing for cell detachment. Although the mechanisms of FA assembly have largely been defined, the molecular circuitry that regulates their disassembly still remains elusive. Results: Here, we show that RN-tre, a GTPase-activating protein (GAP) for Rabs including Rab5 and Rab43, is a novel regulator of FA dynamics and cell migration. RN-tre localizes to FAs and to a pool of Rab5-positive vesicles mainly associated with FAs undergoing rapid remodeling. We found that RN-tre inhibits endocytosis of b1, but not b3, integrins and delays the turnover of FAs, ultimately impairing b1-dependent, but not b3-dependent, chemotactic cell migration. All of these effects are mediated by its GAP activity and rely on Rab5. Conclusions: Our findings identify RN-tre as the Rab5-GAP that spatiotemporally controls FA remodeling during chemotactic cell migration.
Molecular Oncology, Nov 27, 2017
Science Signaling, 2008
The phosphoinositide 3-kinase (PI3K) pathway crucially controls metabolism and cell growth. Altho... more The phosphoinositide 3-kinase (PI3K) pathway crucially controls metabolism and cell growth. Although different PI3K catalytic subunits are known to play distinct roles, the specific in vivo function of p110β (the product of the PIK3CB gene) is not clear. Here, we show that mouse mutants expressing a catalytically inactive PIK3CB K805R mutant survived to adulthood but showed growth retardation and developed mild insulin resistance with age. Pharmacological and genetic analyses of p110β function revealed that p110β catalytic activity is required for PI3K signaling downstream of heterotrimeric guanine nucleotide-binding (G protein)-coupled receptors as well as to sustain long term insulin signaling. In addition, PIK3CB K805R mice were protected in a model of ERBB2-driven tumor development. These findings indicate an unexpected role for p110β catalytic activity in diabetes and cancer, opening potential new avenues for therapeutic intervention.
Cell, Jan 11, 2008
The small GTPases, Rab5 and Rac, are essential for endocytosis and actin remodeling, respectively... more The small GTPases, Rab5 and Rac, are essential for endocytosis and actin remodeling, respectively. Coordination of these processes is critical to achieve spatial restriction of intracellular signaling, which is essential for a variety of polarized functions. Here, we show that clathrin- and Rab5-mediated endocytosis are required for the activation of Rac induced by motogenic stimuli. Rac activation occurs on early endosomes, where the RacGEF Tiam1 is also recruited. Subsequent recycling of Rac to the plasma membrane ensures localized signaling, leading to the formation of actin-based migratory protrusions. Thus, membrane trafficking of Rac is required for the spatial resolution of Rac-dependent motogenic signals. We further demonstrate that a Rab5-to-Rac circuitry controls the morphology of motile mammalian tumor cells and primordial germinal cells during zebrafish development, suggesting that this circuitry is relevant for the regulation of migratory programs in various cells, in b...
Cell Research, 2012
to an adaptor that first interacts at high affinity with Rab5-GTP to promote the selective endocy... more to an adaptor that first interacts at high affinity with Rab5-GTP to promote the selective endocytosis of ligand-bound/ active β1 integrins and then causes the translocation of R-Ras to early endosomes. Here, the R-Ras/RIN2/Rab5 signaling module activates Rac1-dependent cell adhesion via TIAM1, a Rac GEF that localizes on early endosomes and is stimulated by the interaction with both Ras proteins and the vesicular lipid phosphatidylinositol 3-monophosphate. In conclusion, the ability of R-Ras-GTP to convert RIN2 from a GEF to an adaptor that preferentially binds Rab5-GTP allows the triggering of the endocytosis of ECM-bound/active β1 integrins and the ensuing funneling of R-Ras-GTP toward early endosomes to elicit the pro-adhesive and TIAM1-mediated activation of Rac1. R-Ras signals to active integrins and Rac via RIN2 2 npg Cell Research | www.cell-research.com www.cell-research.com | Cell Research Chiara Sandri et al. 3 npg
Molecular Biology Intelligence Unit, 2006
Activation of many receptors triggers a cascade of signal transducing events and increases their ... more Activation of many receptors triggers a cascade of signal transducing events and increases their rate of internalization. Receptor endocytosis has always been viewed primarily as a mechanism to negatively regulate receptor activation, but recent evidence suggests that internalization may result in the formation of specialized signaling platforms on intracellular vesicles. Thus, the investigation of the molecular composition of the various
Cell, Jul 11, 2008
The small GTPases, Rab5 and Rac, are essential for endocytosis and actin remodeling, respectively... more The small GTPases, Rab5 and Rac, are essential for endocytosis and actin remodeling, respectively. Coordination of these processes is critical to achieve spatial restriction of intracellular signaling, which is essential for a variety of polarized functions. Here, we show that clathrin-and Rab5-mediated endocytosis are required for the activation of Rac induced by motogenic stimuli. Rac activation occurs on early endosomes, where the RacGEF Tiam1 is also recruited. Subsequent recycling of Rac to the plasma membrane ensures localized ...
Current Biology, 2013
Integrin-mediated adhesion of cells to the extracellular matrix (ECM) relies on the dynamic forma... more Integrin-mediated adhesion of cells to the extracellular matrix (ECM) relies on the dynamic formation of focal adhesions (FAs), which are biochemical and mechanosensitive platforms composed of a large variety of cytosolic and transmembrane proteins. During migration, there is a constant turnover of ECM contacts that initially form as nascent adhesions at the leading edge, mature into FAs as actomyosin tension builds up, and are then disassembled at the cell rear, thus allowing for cell detachment. Although the mechanisms of FA assembly have largely been defined, the molecular circuitry that regulates their disassembly still remains elusive. Here, we show that RN-tre, a GTPase-activating protein (GAP) for Rabs including Rab5 and Rab43, is a novel regulator of FA dynamics and cell migration. RN-tre localizes to FAs and to a pool of Rab5-positive vesicles mainly associated with FAs undergoing rapid remodeling. We found that RN-tre inhibits endocytosis of β1, but not β3, integrins and delays the turnover of FAs, ultimately impairing β1-dependent, but not β3-dependent, chemotactic cell migration. All of these effects are mediated by its GAP activity and rely on Rab5. Our findings identify RN-tre as the Rab5-GAP that spatiotemporally controls FA remodeling during chemotactic cell migration.
Current Biology, 2013
Background: Integrin-mediated adhesion of cells to the extracellular matrix (ECM) relies on the d... more Background: Integrin-mediated adhesion of cells to the extracellular matrix (ECM) relies on the dynamic formation of focal adhesions (FAs), which are biochemical and mechanosensitive platforms composed of a large variety of cytosolic and transmembrane proteins. During migration, there is a constant turnover of ECM contacts that initially form as nascent adhesions at the leading edge, mature into FAs as actomyosin tension builds up, and are then disassembled at the cell rear, thus allowing for cell detachment. Although the mechanisms of FA assembly have largely been defined, the molecular circuitry that regulates their disassembly still remains elusive. Results: Here, we show that RN-tre, a GTPase-activating protein (GAP) for Rabs including Rab5 and Rab43, is a novel regulator of FA dynamics and cell migration. RN-tre localizes to FAs and to a pool of Rab5-positive vesicles mainly associated with FAs undergoing rapid remodeling. We found that RN-tre inhibits endocytosis of b1, but not b3, integrins and delays the turnover of FAs, ultimately impairing b1-dependent, but not b3-dependent, chemotactic cell migration. All of these effects are mediated by its GAP activity and rely on Rab5. Conclusions: Our findings identify RN-tre as the Rab5-GAP that spatiotemporally controls FA remodeling during chemotactic cell migration.
Molecular Oncology, Nov 27, 2017
Science Signaling, 2008
The phosphoinositide 3-kinase (PI3K) pathway crucially controls metabolism and cell growth. Altho... more The phosphoinositide 3-kinase (PI3K) pathway crucially controls metabolism and cell growth. Although different PI3K catalytic subunits are known to play distinct roles, the specific in vivo function of p110β (the product of the PIK3CB gene) is not clear. Here, we show that mouse mutants expressing a catalytically inactive PIK3CB K805R mutant survived to adulthood but showed growth retardation and developed mild insulin resistance with age. Pharmacological and genetic analyses of p110β function revealed that p110β catalytic activity is required for PI3K signaling downstream of heterotrimeric guanine nucleotide-binding (G protein)-coupled receptors as well as to sustain long term insulin signaling. In addition, PIK3CB K805R mice were protected in a model of ERBB2-driven tumor development. These findings indicate an unexpected role for p110β catalytic activity in diabetes and cancer, opening potential new avenues for therapeutic intervention.
Cell, Jan 11, 2008
The small GTPases, Rab5 and Rac, are essential for endocytosis and actin remodeling, respectively... more The small GTPases, Rab5 and Rac, are essential for endocytosis and actin remodeling, respectively. Coordination of these processes is critical to achieve spatial restriction of intracellular signaling, which is essential for a variety of polarized functions. Here, we show that clathrin- and Rab5-mediated endocytosis are required for the activation of Rac induced by motogenic stimuli. Rac activation occurs on early endosomes, where the RacGEF Tiam1 is also recruited. Subsequent recycling of Rac to the plasma membrane ensures localized signaling, leading to the formation of actin-based migratory protrusions. Thus, membrane trafficking of Rac is required for the spatial resolution of Rac-dependent motogenic signals. We further demonstrate that a Rab5-to-Rac circuitry controls the morphology of motile mammalian tumor cells and primordial germinal cells during zebrafish development, suggesting that this circuitry is relevant for the regulation of migratory programs in various cells, in b...
Cell Research, 2012
to an adaptor that first interacts at high affinity with Rab5-GTP to promote the selective endocy... more to an adaptor that first interacts at high affinity with Rab5-GTP to promote the selective endocytosis of ligand-bound/ active β1 integrins and then causes the translocation of R-Ras to early endosomes. Here, the R-Ras/RIN2/Rab5 signaling module activates Rac1-dependent cell adhesion via TIAM1, a Rac GEF that localizes on early endosomes and is stimulated by the interaction with both Ras proteins and the vesicular lipid phosphatidylinositol 3-monophosphate. In conclusion, the ability of R-Ras-GTP to convert RIN2 from a GEF to an adaptor that preferentially binds Rab5-GTP allows the triggering of the endocytosis of ECM-bound/active β1 integrins and the ensuing funneling of R-Ras-GTP toward early endosomes to elicit the pro-adhesive and TIAM1-mediated activation of Rac1. R-Ras signals to active integrins and Rac via RIN2 2 npg Cell Research | www.cell-research.com www.cell-research.com | Cell Research Chiara Sandri et al. 3 npg
Molecular Biology Intelligence Unit, 2006
Activation of many receptors triggers a cascade of signal transducing events and increases their ... more Activation of many receptors triggers a cascade of signal transducing events and increases their rate of internalization. Receptor endocytosis has always been viewed primarily as a mechanism to negatively regulate receptor activation, but recent evidence suggests that internalization may result in the formation of specialized signaling platforms on intracellular vesicles. Thus, the investigation of the molecular composition of the various
Cell, Jul 11, 2008
The small GTPases, Rab5 and Rac, are essential for endocytosis and actin remodeling, respectively... more The small GTPases, Rab5 and Rac, are essential for endocytosis and actin remodeling, respectively. Coordination of these processes is critical to achieve spatial restriction of intracellular signaling, which is essential for a variety of polarized functions. Here, we show that clathrin-and Rab5-mediated endocytosis are required for the activation of Rac induced by motogenic stimuli. Rac activation occurs on early endosomes, where the RacGEF Tiam1 is also recruited. Subsequent recycling of Rac to the plasma membrane ensures localized ...
Current Biology, 2013
Integrin-mediated adhesion of cells to the extracellular matrix (ECM) relies on the dynamic forma... more Integrin-mediated adhesion of cells to the extracellular matrix (ECM) relies on the dynamic formation of focal adhesions (FAs), which are biochemical and mechanosensitive platforms composed of a large variety of cytosolic and transmembrane proteins. During migration, there is a constant turnover of ECM contacts that initially form as nascent adhesions at the leading edge, mature into FAs as actomyosin tension builds up, and are then disassembled at the cell rear, thus allowing for cell detachment. Although the mechanisms of FA assembly have largely been defined, the molecular circuitry that regulates their disassembly still remains elusive. Here, we show that RN-tre, a GTPase-activating protein (GAP) for Rabs including Rab5 and Rab43, is a novel regulator of FA dynamics and cell migration. RN-tre localizes to FAs and to a pool of Rab5-positive vesicles mainly associated with FAs undergoing rapid remodeling. We found that RN-tre inhibits endocytosis of β1, but not β3, integrins and delays the turnover of FAs, ultimately impairing β1-dependent, but not β3-dependent, chemotactic cell migration. All of these effects are mediated by its GAP activity and rely on Rab5. Our findings identify RN-tre as the Rab5-GAP that spatiotemporally controls FA remodeling during chemotactic cell migration.