Schematic structures of key PIP₂ or IP₃ kinases and PIP₂ lipases in lymphocytes. For details, see text.

The phosphoinositide PI(4,5)P₂ is a key node of second messenger metabolism in lymphocytes. PI(4,5)P₂-phosphorylation by PI3-kinases and PI(4,5)P₂-hydrolysis by PLCγ initiate several second messenger cascades within cellular membranes and soluble compartments. These second messengers can have various functions, including the recruitment and/or activation of effector proteins by binding to specific domains within them (blue arrows and green boxes). In particular, the phosphatases SHIP1/2 or PTEN limit or down-regulate PIP₃ levels and the functions of PIP₃ and its effectors by hydrolyzing PIP₃ into PI(3,4)P₂ or PI(4,5)P₂, respectively. For group 1D, PH domains such as that of Akt, PI(3,4)P₂ binding sustains effector activity (Cozier et al. 2004; DiNitto and Lambright 2006; Lemmon 2008). PI(4,5)P₂ recruits proteins such as RASA3/GAP1^IP4BP by binding to their PH domains (Lockyer et al. 1997; Cozier et al. 2000a; Cozier et al. 2000b). Hence, both PIP₂s and PIP₃ can have partially overlapping functions depending on the lipid-binding protein domain involved. PLCγ hydrolyzes PI(4,5)P₂ into protein C1 domain binding DAG and into IP₃, which binds EF and C2 domain containing proteins and mobilizes Ca²⁺. IP₃ 3-kinases convert IP₃ into IP₄, which acts as a soluble PIP₃ analog and controls the abilities of certain PH domains to bind to PIP₃ either positively (green arrow) or negatively (red arrow). An unknown 5-phosphatase metabolizes IP₄ into I(1,3,4)P₃, a precursor for higher-order IPs. In vitro, SHIP1 and PTEN can dephosphorylate IP₄ at the 5- or 3-positions, respectively (Erneux et al. 1998; Maehama and Dixon 1998; Pesesse et al. 1998; Caffrey et al. 2001). Whether this occurs physiologically is unknown. Finally, DAG kinases (DGKs) down-regulate DAG function by phosphorylating it into PA, itself a ligand for certain proteins. Further metabolism of all these second messengers results in the generation of many lipid and soluble metabolites. Several of these have important signaling functions (Irvine 2001; Irvine and Schell 2001; York and Hunter 2004; York 2006; Alcazar-Roman and Wente 2008; Huang et al. 2008; Jia et al. 2008b; Miller et al. 2008; Burton et al. 2009; Shears 2009; Sauer and Cooke 2010; Schell 2010). Their functions in immunocytes are unknown.

Schematic structures of key PIP₃ or IP₄ phosphatases and DAG kinases in lymphocytes. For details, see text.