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Molecular and Cellular Biology, February 2007, p. 854-863, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.01400-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Intramolecular Regulation of Phospholipase C-{gamma}1 by Its C-Terminal Src Homology 2 Domain{triangledown}

Karen DeBell,1 Laurie Graham,1 Ilona Reischl,1,{dagger} Carmen Serrano,1,{ddagger} Ezio Bonvini,2 and Barbara Rellahan1*

Laboratory of Immunobiology, Division of Monoclonal Antibodies, Center for Drugs Evaluation and Research, Food and Drug Administration, Bethesda, Maryland,1 MacroGenics, Inc., 1500 East Gude Drive, Rockville, Maryland2

Received 31 July 2006/ Returned for modification 7 October 2006/ Accepted 11 November 2006

Phosphoinositide-specific phospholipase C-{gamma}1 (PLC-{gamma}1) is a key enzyme that governs cellular functions such as gene transcription, secretion, proliferation, motility, and development. Here, we show that PLC-{gamma}1 is regulated via a novel autoinhibitory mechanism involving its carboxy-terminal Src homology (SH2C) domain. Mutation of the SH2C domain tyrosine binding site led to constitutive PLC-{gamma}1 activation. The amino-terminal split pleckstrin homology (sPHN) domain was found to regulate the accessibility of the SH2C domain. PLC-{gamma}1 constructs with mutations in tyrosine 509 and phenylalanine 510 in the sPHN domain no longer required an intact amino-terminal Src homology (SH2N) domain or phosphorylation of tyrosine 775 or 783 for activation. These data are consistent with a model in which the SH2C domain is blocked by an intramolecular interaction(s) that is released upon cellular activation by occupancy of the SH2N domain.

* Corresponding author. Mailing address: DMA/OPS/CDER/FDA, NIH Bldg. 29B, 3NN06, 29 Lincoln Drive, Bethesda, MD 20892-4555. Phone: (301) 827-0715. Fax: (301) 827-0852. E-mail: barbara.rellahan{at}fda.hhs.gov.

{triangledown} Published ahead of print on 20 November 2006.

{dagger} Present address: AGES/PharmMED, Institute for Science and Information, Schnirchgasse 9, A-1030 Vienna, Austria.

{ddagger} Present address: Unidad de Medicina y Ciencias de la Salud, Universidad Autonoma de Zacatecas, Carretera a la Bufa No 1, Altos, Zacatecas, Zac 98000, Mexico.

Molecular and Cellular Biology, February 2007, p. 854-863, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.01400-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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