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PMID: 15767666 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Molecular and cellular biology ·Vol. 25 ·No. 7 ·2005-04-00 ·Pages 2593-606

Brachmann SM, Yballe CM, Innocenti M, Deane JA, Fruman DA, Thomas SM, Cantley LC

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 p85alpha gene (p85alpha-/- p55alpha-/- p50alpha-/-) or in mice lacking the p85beta gene (p85beta-/-) (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 alpha null (PDGFRalpha-/-) mice (P. Soriano, Development 124:2691-2700, 1997), suggesting that PI3K is an essential mediator of PDGFRalpha signaling at this developmental stage. p85alpha-/- p55alpha+/+ p50alpha+/+ p85beta-/- mice had similar but less severe defects, indicating that p85alpha and p85beta have a critical and redundant function in development. Mouse embryo fibroblasts deficient in all p85alpha and p85beta gene products (p85alpha-/- p55alpha-/- p50alpha-/- p85beta-/-) are defective in PDGF-induced membrane ruffling. Overexpression of the Rac-specific GDP-GTP exchange factor Vav2 or reintroduction of p85alpha or p85beta rescues the membrane ruffling defect. Surprisingly, reintroduction of p50alpha also restored PDGF-dependent 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 p50alpha, are not required for this response.

MeSH Terms
Actins/metabolism Animals Cell Membrane/drug effects,genetics,metabolism Cell Surface Extensions/drug effects Embryo Loss/enzymology,genetics,metabolism Embryo, Mammalian/embryology,enzymology,metabolism Extracellular Signal-Regulated MAP Kinases/metabolism Isoenzymes/chemistry,deficiency,genetics,metabolism Mice Mice, Knockout Molecular Weight Phosphatidylinositol 3-Kinases/chemistry,deficiency,genetics,metabolism Phosphorylation Platelet-Derived Growth Factor/pharmacology Protein Serine-Threonine Kinases/metabolism Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-akt Signal Transduction
Chemicals
Actins Isoenzymes Platelet-Derived Growth Factor Proto-Oncogene Proteins Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Extracellular Signal-Regulated MAP Kinases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Brachmann Saskia M
Beth Israel Hospital, NRB, Division of Signal Transduction, Department of Systems Biology,10th Floor, 330 Brookline, MA 02215, USA.
Yballe Claudine M
Innocenti Metello
Deane Jonathan A
Fruman David A
Thomas Sheila M
Cantley Lewis C
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.25.7.2593-2606.2005
Published
2005-04-00
Pages
2593-606
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1061637
Subset
IM
Grants
NIAID NIH HHS · R01 AI050831 · United States
NIGMS NIH HHS · R37 GM041890 · United States
NIGMS NIH HHS · R01 GM041890 · United States
NIAID NIH HHS · AI50831 · United States
NCI NIH HHS · P01-CA089021 · United States
NCI NIH HHS · CA75621 · United States
NCI NIH HHS · P01 CA089021 · United States
NIGMS NIH HHS · GM41890 · United States
External Links
PubMed source DOI: 10.1128/MCB.25.7.2593-2606.2005 PMC Full Text View journal details
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