Intramolecular regulation of phospholipase C-gamma1 by its C-terminal Src homology 2 domain.
Phosphoinositide-specific phospholipase C-gamma1 (PLC-gamma1) is a key enzyme that governs cellular functions such as gene transcription, secretion, proliferation, motility, and development. Here, we show that PLC-gamma1 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-gamma1 activation. The amino-terminal split pleckstrin homology (sPHN) domain was found to regulate the accessibility of the SH2C domain. PLC-gamma1 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.
DeBell
Karen
K
Laboratory of Immunobiology, Division of Monoclonal Antibodies, Centrer for Drug Evaluation and Research, Food and Drug Administration/DHHS, 29 Lincoln Drive, Bethesda, MD 20892-4555, USA. barbara.rellahan@fda.hhs.gov.
Graham
Laurie
L
Reischl
Ilona
I
Serrano
Carmen
C
Bonvini
Ezio
E
Rellahan
Barbara
B
D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D020013:Calcium Signaling; D002384:Catalysis; D002417:Cattle; D002645:Chickens; D006801:Humans; D007700:Kinetics; D021962:Membrane Microdomains / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010649:Phenylalanine / Q000235:genetics / Q000378:metabolism; D051966:Phospholipase C gamma / Q000737:chemistry* / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D018909:src Homology Domains
D010750:Phosphoproteins; D011947:Receptors, Antigen, B-Cell; D019000:Phosphotyrosine; D010649:Phenylalanine; D051966:Phospholipase C gamma