Class Ia phosphoinositide 3-kinases (PI3Ks) are heterodimers of p110 catalytic and p85 regulatory subunits that mediate a variety of cellular responses to growth and differentiation factors. Although embryonic development is not impaired in mice lacking all isoforms of the p85α gene (p85α-/- p55α-/- p50α-/-) or in mice lacking the p85β gene (p85β-/-) (D. A. Fruman, F. Mauvais-Jarvis, D. A. Pollard, C. M. Yballe, D. Brazil, R. T. Bronson, C. R. Kahn, and L. C. Cantley, Nat Genet. 26:379-382, 2000; K. Ueki, C. M. Yballe, S. M. Brachmann, D. Vicent, J. M. Watt, C. R. Kahn, and L. C. Cantley, Proc. Natl. Acad. Sci. USA 99:419-424, 2002), we show here that loss of both genes results in lethality at embryonic day 12.5 (E12.5). The phenotypes of these embryos, including subepidermal blebs flanking the neural tube at E8 and bleeding into the blebs during the turning process, are similar to defects observed in platelet-derived growth factor receptor α null (PDGFRα -/-) mice (P. Soriano, Development 124:2691-2700, 1997), suggesting that PI3K is an essential mediator of PDGFRα signaling at this developmental stage. p85α-/- p55α+/+ p50α+/+ p85β-/- mice had similar but less severe defects, indicating that p85α and p85β have a critical and redundant function in development. Mouse embryo fibroblasts deficient in all p85α and p85β gene products (p85α-/- p55α-/- p50α-/- p85α-/-) are defective in PDGF-induced membrane ruffling. Overespression of the Rac-specific GDP-GTP exchange factor Vav2 or reintroduction of p85α or p85β rescues the membrane ruffling defect Surprisingly, reintroduction of p50α also restored PDGF-dcpendcnt membrane ruffling. These results indicate that class Ia PI3K is critical for PDGF-dependent actin rearrangement but that the SH3 domain and the Rho/Rac/Cdc42-interacting domain of p85, which lacks p50α, are not required for this response.

Brachmann, S., Yballe, C., Innocenti, M., Deane, J., Fruman, D., Thomas, S., et al. (2005). Role of phosphoinositide 3-kinase regulatory isoforms in development and actin rearrangement. MOLECULAR AND CELLULAR BIOLOGY, 25(7), 2593-2606 [10.1128/MCB.25.7.2593-2606.2005].

Role of phosphoinositide 3-kinase regulatory isoforms in development and actin rearrangement

Innocenti M;
2005

Abstract

Class Ia phosphoinositide 3-kinases (PI3Ks) are heterodimers of p110 catalytic and p85 regulatory subunits that mediate a variety of cellular responses to growth and differentiation factors. Although embryonic development is not impaired in mice lacking all isoforms of the p85α gene (p85α-/- p55α-/- p50α-/-) or in mice lacking the p85β gene (p85β-/-) (D. A. Fruman, F. Mauvais-Jarvis, D. A. Pollard, C. M. Yballe, D. Brazil, R. T. Bronson, C. R. Kahn, and L. C. Cantley, Nat Genet. 26:379-382, 2000; K. Ueki, C. M. Yballe, S. M. Brachmann, D. Vicent, J. M. Watt, C. R. Kahn, and L. C. Cantley, Proc. Natl. Acad. Sci. USA 99:419-424, 2002), we show here that loss of both genes results in lethality at embryonic day 12.5 (E12.5). The phenotypes of these embryos, including subepidermal blebs flanking the neural tube at E8 and bleeding into the blebs during the turning process, are similar to defects observed in platelet-derived growth factor receptor α null (PDGFRα -/-) mice (P. Soriano, Development 124:2691-2700, 1997), suggesting that PI3K is an essential mediator of PDGFRα signaling at this developmental stage. p85α-/- p55α+/+ p50α+/+ p85β-/- mice had similar but less severe defects, indicating that p85α and p85β have a critical and redundant function in development. Mouse embryo fibroblasts deficient in all p85α and p85β gene products (p85α-/- p55α-/- p50α-/- p85α-/-) are defective in PDGF-induced membrane ruffling. Overespression of the Rac-specific GDP-GTP exchange factor Vav2 or reintroduction of p85α or p85β rescues the membrane ruffling defect Surprisingly, reintroduction of p50α also restored PDGF-dcpendcnt membrane ruffling. These results indicate that class Ia PI3K is critical for PDGF-dependent actin rearrangement but that the SH3 domain and the Rho/Rac/Cdc42-interacting domain of p85, which lacks p50α, are not required for this response.
Articolo in rivista - Articolo scientifico
PI3K; cytoskeleton; GTPases; cell signalling; actin
English
2593
2606
14
Brachmann, S., Yballe, C., Innocenti, M., Deane, J., Fruman, D., Thomas, S., et al. (2005). Role of phosphoinositide 3-kinase regulatory isoforms in development and actin rearrangement. MOLECULAR AND CELLULAR BIOLOGY, 25(7), 2593-2606 [10.1128/MCB.25.7.2593-2606.2005].
Brachmann, S; Yballe, C; Innocenti, M; Deane, J; Fruman, D; Thomas, S; Cantley, L
File in questo prodotto:
File Dimensione Formato  
Brachmann-2005-Mol Cell Biol-VoR.pdf

Solo gestori archivio

Descrizione: Article
Tipologia di allegato: Publisher’s Version (Version of Record, VoR)
Dimensione 914.37 kB
Formato Adobe PDF
914.37 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/396452
Citazioni
  • Scopus 106
  • ???jsp.display-item.citation.isi??? 106
Social impact