PI3K phosphorylates PIP2 to PIP3 A number of different extracellular signals converge on PI3K activation. PI3K can be activated downstream of receptor tyrosine kinases (RTKs) such as FGFR (Ong et al. 2001, Eswarakumar et al. 2005), KIT (Chian et al. 2001, Ronnstrand 2004, Reber et al. 2006), PDGF (Coughlin et al. 1989, Fantl et al. 1992, Heldin et al. 1998), insulin receptor IGF1R (Hadari et al. 1992, Kooijman et al. 1995), and EGFR and its family members (Rodrigues et al. 2000, Jackson et al. 2004, Kainulainen et al. 2000, Junttila et al. 2009). Other proteins, such as CD28 (Pages et al. 1996, Koyasu 2003, Kane and Weiss, 2003) and TRAT1 (Bruyns et al. 1998, Koyasu 2003, Kolsch et al. 2006), can also trigger PI3K activity.<br><br>In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011). Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.1.153 Edited: Matthews, L, 2012-08-03 Pubmed10648629 Pubmed10722704 Pubmed11353842 Pubmed11520784 Pubmed12660731 Pubmed12670391 Pubmed1374684 Pubmed1381348 Pubmed15059917 Pubmed15526160 Pubmed15863030 Pubmed16483568 Pubmed16612002 Pubmed19411071 Pubmed19805105 Pubmed21827948 Pubmed2466336 Pubmed7543144 Pubmed8621607 Pubmed9687533 Pubmed9739761 Reactome Database ID Release 432316434 Reactome, http://www.reactome.org ReactomeREACT_147781 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13