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Role of Phosphoinositide 3-Kinase Regulatory Isoforms in Development and Actin Rearrangement

Division of Signal Transduction, Department of Systems Biology,¹ Cancer Biology Program, Department of Medicine, Beth Israel Deaconness Medical Center, Harvard Medical School, Boston, Massachusetts,⁵ Center for Immunology and Department of Molecular Biology and Biochemistry, University of California—Irvine, Irvine, California,⁴ Institut fuer Biochemie, Freie Universitaet Berlin, Berlin, Germany,² Department of Experimental Oncology, European Institute of Oncology, Milan, Italy³

Received 14 August 2004/ Returned for modification 4 October 2004/ Accepted 20 December 2004

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 p85 gene (p85^–/– p55^–/– p50^–/–) or in mice lacking the p85ß gene (p85ß^–/–) (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 null (PDGFR^–/–) mice (P. Soriano, Development 124:2691-2700, 1997), suggesting that PI3K is an essential mediator of PDGFR signaling at this developmental stage. p85^–/– p55^+/+ p50^+/+ p85ß^–/– mice had similar but less severe defects, indicating that p85 and p85ß have a critical and redundant function in development. Mouse embryo fibroblasts deficient in all p85 and p85ß gene products (p85^–/– p55^–/– p50^–/– p85ß^–/–) are defective in PDGF-induced membrane ruffling. Overexpression of the Rac-specific GDP-GTP exchange factor Vav2 or reintroduction of p85 or p85ß rescues the membrane ruffling defect. Surprisingly, reintroduction of p50 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 p50, are not required for this response.

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