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Role of the PI3K regulatory subunit in the control of actin organization and cell migration.

Jiménez C, Portela RA, Mellado M, Rodríguez-Frade JM, Collard J, Serrano A, Martínez-A C, Avila J, Carrera AC - J. Cell Biol. (2000)

Bottom Line: We demonstrate that PDGF activates Cdc42 and its downstream effector N-WASP to mediate filopodia formation, actin stress fiber disassembly, and a reduction in focal adhesion complexes.Induction of the Cdc42 pathway is independent of phosphoinositide 3-kinase (PI3K) enzymatic activity, but it is dependent on the p85alpha regulatory subunit of PI3K.Finally, data are provided showing that activation of this pathway is required for PDGF-induced cell migration on collagen.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología, Madrid, Spain.

ABSTRACT
Cell migration represents an important cellular response that utilizes cytoskeletal reorganization as its driving force. Here, we describe a new signaling cascade linking PDGF receptor stimulation to actin rearrangements and cell migration. We demonstrate that PDGF activates Cdc42 and its downstream effector N-WASP to mediate filopodia formation, actin stress fiber disassembly, and a reduction in focal adhesion complexes. Induction of the Cdc42 pathway is independent of phosphoinositide 3-kinase (PI3K) enzymatic activity, but it is dependent on the p85alpha regulatory subunit of PI3K. Finally, data are provided showing that activation of this pathway is required for PDGF-induced cell migration on collagen. These observations show the essential role of the PI3K regulatory subunit p85alpha in controlling PDGF receptor-induced cytoskeletal changes and cell migration, illustrating a novel signaling pathway that links receptor stimulation at the cell membrane with actin dynamics.

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PDGF-PI3K–derived pathways that affect cytoskeletal organization and cell migration. Model illustrating the signaling pathways initiated by the PDGF-R that affect actin cytoskeleton and cell migration, including the previously described p110/PI3K activity–dependent Rac pathway, which promotes lamellipodial extensions and the novel p85-PI3K regulatory subunit-triggered Cdc42 pathway. Activation of the Rac pathway triggers a number of effectors, of which Por 1, inducing lamellipodium formation, and Pak, mediating inhibition of actin stress fibers in v-Rac and v-Cdc42–expressing cells, are indicated (Lim et al. 1996; Van Aelst et al. 1996). Activation of the Cdc42 pathway also triggers a number of effectors of which, N-WASP promotes filopodia formation, and contributes to mediate the decrease in actin stress fibers and adhesion complexes induced by PDGF. Induction of both pathways control PDGF-induced cell migration on collagen.
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Figure 10: PDGF-PI3K–derived pathways that affect cytoskeletal organization and cell migration. Model illustrating the signaling pathways initiated by the PDGF-R that affect actin cytoskeleton and cell migration, including the previously described p110/PI3K activity–dependent Rac pathway, which promotes lamellipodial extensions and the novel p85-PI3K regulatory subunit-triggered Cdc42 pathway. Activation of the Rac pathway triggers a number of effectors, of which Por 1, inducing lamellipodium formation, and Pak, mediating inhibition of actin stress fibers in v-Rac and v-Cdc42–expressing cells, are indicated (Lim et al. 1996; Van Aelst et al. 1996). Activation of the Cdc42 pathway also triggers a number of effectors of which, N-WASP promotes filopodia formation, and contributes to mediate the decrease in actin stress fibers and adhesion complexes induced by PDGF. Induction of both pathways control PDGF-induced cell migration on collagen.

Mentions: Actin cytoskeleton reorganization is an essential process required for cell migration. Here, we describe that stimulation of PDGF-R on fibroblasts activates Cdc42 and its effector N-WASP inducing filopodia formation, a decrease in actin stress fibers and a reduction in focal adhesion complexes. The data presented also support that p85α, the regulatory subunit of PI3K, is capable of activating the Cdc42/N-WASP pathway linking PDGF-R stimulation to Cdc42 activation. These data, integrated into the model depicted in Fig. 10, include the novel description on PDGF's ability to activate Cdc42 and a new role for the PI3K regulatory subunit in controlling actin dynamics and cell migration.


Role of the PI3K regulatory subunit in the control of actin organization and cell migration.

Jiménez C, Portela RA, Mellado M, Rodríguez-Frade JM, Collard J, Serrano A, Martínez-A C, Avila J, Carrera AC - J. Cell Biol. (2000)

PDGF-PI3K–derived pathways that affect cytoskeletal organization and cell migration. Model illustrating the signaling pathways initiated by the PDGF-R that affect actin cytoskeleton and cell migration, including the previously described p110/PI3K activity–dependent Rac pathway, which promotes lamellipodial extensions and the novel p85-PI3K regulatory subunit-triggered Cdc42 pathway. Activation of the Rac pathway triggers a number of effectors, of which Por 1, inducing lamellipodium formation, and Pak, mediating inhibition of actin stress fibers in v-Rac and v-Cdc42–expressing cells, are indicated (Lim et al. 1996; Van Aelst et al. 1996). Activation of the Cdc42 pathway also triggers a number of effectors of which, N-WASP promotes filopodia formation, and contributes to mediate the decrease in actin stress fibers and adhesion complexes induced by PDGF. Induction of both pathways control PDGF-induced cell migration on collagen.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2192656&req=5

Figure 10: PDGF-PI3K–derived pathways that affect cytoskeletal organization and cell migration. Model illustrating the signaling pathways initiated by the PDGF-R that affect actin cytoskeleton and cell migration, including the previously described p110/PI3K activity–dependent Rac pathway, which promotes lamellipodial extensions and the novel p85-PI3K regulatory subunit-triggered Cdc42 pathway. Activation of the Rac pathway triggers a number of effectors, of which Por 1, inducing lamellipodium formation, and Pak, mediating inhibition of actin stress fibers in v-Rac and v-Cdc42–expressing cells, are indicated (Lim et al. 1996; Van Aelst et al. 1996). Activation of the Cdc42 pathway also triggers a number of effectors of which, N-WASP promotes filopodia formation, and contributes to mediate the decrease in actin stress fibers and adhesion complexes induced by PDGF. Induction of both pathways control PDGF-induced cell migration on collagen.
Mentions: Actin cytoskeleton reorganization is an essential process required for cell migration. Here, we describe that stimulation of PDGF-R on fibroblasts activates Cdc42 and its effector N-WASP inducing filopodia formation, a decrease in actin stress fibers and a reduction in focal adhesion complexes. The data presented also support that p85α, the regulatory subunit of PI3K, is capable of activating the Cdc42/N-WASP pathway linking PDGF-R stimulation to Cdc42 activation. These data, integrated into the model depicted in Fig. 10, include the novel description on PDGF's ability to activate Cdc42 and a new role for the PI3K regulatory subunit in controlling actin dynamics and cell migration.

Bottom Line: We demonstrate that PDGF activates Cdc42 and its downstream effector N-WASP to mediate filopodia formation, actin stress fiber disassembly, and a reduction in focal adhesion complexes.Induction of the Cdc42 pathway is independent of phosphoinositide 3-kinase (PI3K) enzymatic activity, but it is dependent on the p85alpha regulatory subunit of PI3K.Finally, data are provided showing that activation of this pathway is required for PDGF-induced cell migration on collagen.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología, Madrid, Spain.

ABSTRACT
Cell migration represents an important cellular response that utilizes cytoskeletal reorganization as its driving force. Here, we describe a new signaling cascade linking PDGF receptor stimulation to actin rearrangements and cell migration. We demonstrate that PDGF activates Cdc42 and its downstream effector N-WASP to mediate filopodia formation, actin stress fiber disassembly, and a reduction in focal adhesion complexes. Induction of the Cdc42 pathway is independent of phosphoinositide 3-kinase (PI3K) enzymatic activity, but it is dependent on the p85alpha regulatory subunit of PI3K. Finally, data are provided showing that activation of this pathway is required for PDGF-induced cell migration on collagen. These observations show the essential role of the PI3K regulatory subunit p85alpha in controlling PDGF receptor-induced cytoskeletal changes and cell migration, illustrating a novel signaling pathway that links receptor stimulation at the cell membrane with actin dynamics.

Show MeSH
Related in: MedlinePlus