THE hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP₂) is a widespread receptor-coupled signalling system at the plasma membrane of most eukaryotic cells. The existence of an entirely separate nuclear phosphoinositide signalling system is suggested from evidence that purified nuclei synthesize PtdInsP₂and phosphatidylinositol 4-phosphate (PtdlnsP) in vitro¹and that a transient decrease in the mass of these lipids occurs when Swiss 3T3 cells are cultured in the presence of insulin-like growth factor-1 (IGF-1)^2–4. These IGF-1-dependent changes in inositol lipids coincide with an increase in nuclear diacylglycerol⁴ and precede translocation to the nucleus and activation of protein kinase C (refs 5, 6). Circumstantial evidence that links these changes with mitosis comes from the isolation of a 3T3 clone that expresses the type-1 IGF receptor and binds IGF-1 peptide but does not respond mitogenically or show transient mass changes in nuclear inositol lipids⁷. A key question is how IGF-1 initiates the rapid breakdown of PtdlnsP and PtdlnsP², in the nucleus. Here we present evidence that nuclei of 3T3 cells contain the β-isozyme of phosphoinositidase C, whereas the γ-isozyme is confined to the cytoplasm and that IGF-1 treatment stimulates exclusively the activity of nuclear phosphoinositidase C.