Depending on the specific subfamily in question, activation can be highly variable. Activation by either Gαq or Gβγ G-protein subunits (making it part of a G protein-coupled receptor signal transduction pathway) or by transmembrane receptors with intrinsic or associated tyrosine kinase activity has been reported. In addition, members of the Ras superfamily of small GTPases (namely the Ras and Rho subfamilies) have also been implicated. It should also be mentioned that all forms of phospholipase C require calcium for activation, many of them possessing multiple calcium contact sites in the catalytic region. The only isoform that is known to be inactive at basal intracellular calcium levels is the δ subfamily of enzymes suggesting that they function as calcium amplifiers that become activated downstream of other PLC family members. PLC-β PLC-β(1-4) (120-155kDa) are activated by Gαq subunits through their C2 domain and long C-terminal extension. Gβγ subunits are known to activate the β2 and β3 isozymes only; however, this occurs through the PH domain and/or through interactions with the catalytic domain. The exact mechanism still requires further investigation. The PH domain of β2 and β3 plays a dual role, much like PLC-δ1, by binding to the plasma membrane, as well as being a site of interaction for the catalytic activator. However, PLC-β binds to the lipid surface independent of PIP2 with all isozymes preferring phosphoinositol-3-phosphate or neutral membranes. Members of the Rho GTPase family (e.g., Rac1, Rac2, Rac3, and cdc42) have been implicated in their activation by binding to an alternate site on the N-terminal PH domain followed by subsequent recruitment to the plasma membrane. A crystal structure of Rac1 bound to the PH domain of PLCβ2 has been solved. Like PLC-δ1, many PLC-β isoforms (in particular, PLC-β1) have been found to take up residence in the nuclear compartment. A basic amino acid region within the enzyme's long C-terminal tail appears to function as a Nuclear Localization Signal for import into the nucleus. PLC-β1 seems to play unspecified roles in cellular proliferation and differentiation. PLC-γ PLC-γ (120-155kDa) is activated by receptor and non-receptor tyrosine kinases due to the presence of two SH2 and a single SH3 domain situated between a split PH domain within the linker region. Although this particular isoform does not contain classic nuclear export or localization sequences, it has been found within the nucleus of certain cell lines. There are two main isoforms of PLCγ expressed in human