Development - PIP3 signaling in cardiac myocytes

PIP3 signaling in cardiac myocytes

Phosphoinositide 3-kinase (PI3K) can be activated in cardiac myocytes by the receptors with intrinsic tyrosine kinase activity, such as insulin receptor (INSR), growth factor receptors (IGF1 receptor and HGF receptor), and by the G protein-coupled receptors (GPCRs).

INSR and IGF1 receptor engagement triggers receptor activation and autophosphorylation. The activated receptor can then phosphorylate several intracellular protein substrates, most notably the insulin receptor substrate (IRS1-4) proteins. Tyrosine-phosphorylated IRS1 can recruit and activate the downstream effector, PI3K, which generates phosphatidylinositol 3,4,5-trisphosphate (PIP3) using inositol-containing phospholipids resident in the plasma membrane as substrates. IRS proteins also recruit adaptors Shc and Grb-2 [1].

The protein tyrosine phosphatase PTP1B is responsible for negatively regulating INSR signaling by dephosphorylating the phosphotyrosine residues of this receptor [2].

Hepatocyte growth factor receptor (HGF receptor) activation induces the tyrosine phosphorylation of GAB1 and its association with PI3K via the recruitment of its regulatory subunit (PI3KR class 1A) that stimulates its catalytic subunit (PI3KC class 1A) [3].

Activated adaptors Shc and Grb-2 recruit exchange factor SOS that activates H-RAS [4]. H-RAS directly stimulates PI3K catalytic subunit (PI3KC class 1A) [5].

PI3K converts phosphatidylinositol 4,5-biphosphate (PI(4,5)P2) to PIP3 [6]. PIP3 is the second messenger that activates diverse signal cascades, including PDK and AKT pathway [6], [7].

Phosphatase PTEN acts as a negative regulator for the PI3K/AKT signaling pathway, converting PI(3,4,5)P3 into PI(4,5)P2 [8].

AKT and PDK phosphorylate diverse proteins that mediate various insulin- and growth factor-induced cellular responses such as glycogen synthesis, protein synthesis, cell cycle initiation, and promotion of cell survival by regulation of apoptosis factors such as BAD and Bcl-x(L) [9], [10], [11].

References:

1. Tseng YH, Ueki K, Kriauciunas KM, Kahn CR
   Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. The Journal of biological chemistry 2002 Aug 30;277(35):31601-11
2. Salmeen A, Andersen JN, Myers MP, Tonks NK, Barford D
   Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. Molecular cell 2000 Dec;6(6):1401-12
3. Lecoq-Lafon C, Verdier F, Fichelson S, Chrétien S, Gisselbrecht S, Lacombe C, Mayeux P
   Erythropoietin induces the tyrosine phosphorylation of GAB1 and its association with SHC, SHP2, SHIP, and phosphatidylinositol 3-kinase. Blood 1999 Apr 15;93(8):2578-85
4. Kuemmerle JF
   IGF-I elicits growth of human intestinal smooth muscle cells by activation of PI3K, PDK-1, and p70S6 kinase. American journal of physiology. Gastrointestinal and liver physiology 2003 Mar;284(3):G411-22
5. Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, Waterfield MD, Downward J
   Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation. The EMBO journal 1996 May 15;15(10):2442-51
6. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
   Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
7. Lemmon MA
   Phosphoinositide recognition domains. Traffic (Copenhagen, Denmark) 2003 Apr;4(4):201-13
8. Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J, Gavrilova N, Mueller B, Liu X, Wu H
   PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proceedings of the National Academy of Sciences of the United States of America 1999 May 25;96(11):6199-204
9. Sakoda H, Gotoh Y, Katagiri H, Kurokawa M, Ono H, Onishi Y, Anai M, Ogihara T, Fujishiro M, Fukushima Y, Abe M, Shojima N, Kikuchi M, Oka Y, Hirai H, Asano T
   Differing roles of Akt and serum- and glucocorticoid-regulated kinase in glucose metabolism, DNA synthesis, and oncogenic activity. The Journal of biological chemistry 2003 Jul 11;278(28):25802-7
10. Chong ZZ, Kang JQ, Maiese K
    AKT1 drives endothelial cell membrane asymmetry and microglial activation through Bcl-xL and caspase 1, 3, and 9. Experimental cell research 2004 Jun 10;296(2):196-207
11. Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G, Calabretta B, Baserga R
    Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis. Molecular and cellular biology 1999 Oct;19(10):7203-15