Kitamura T, Kitamura Y, Kuroda S, Hino Y, Ando M, Kotani K, Konishi H, Matsuzaki H, Kikkawa U, Ogawa W, Kasuga M.; ''Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt.''; PubMedEurope PMCScholia
Hadari YR, Tzahar E, Nadiv O, Rothenberg P, Roberts CT, LeRoith D, Yarden Y, Zick Y.; ''Insulin and insulinomimetic agents induce activation of phosphatidylinositol 3'-kinase upon its association with pp185 (IRS-1) in intact rat livers.''; PubMedEurope PMCScholia
Akdis M, Burgler S, Crameri R, Eiwegger T, Fujita H, Gomez E, Klunker S, Meyer N, O'Mahony L, Palomares O, Rhyner C, Ouaked N, Schaffartzik A, Van De Veen W, Zeller S, Zimmermann M, Akdis CA.; ''Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases.''; PubMedEurope PMCScholia
Anderson KE, Coadwell J, Stephens LR, Hawkins PT.; ''Translocation of PDK-1 to the plasma membrane is important in allowing PDK-1 to activate protein kinase B.''; PubMedEurope PMCScholia
Ahmad F, Cong LN, Stenson Holst L, Wang LM, Rahn Landstrom T, Pierce JH, Quon MJ, Degerman E, Manganiello VC.; ''Cyclic nucleotide phosphodiesterase 3B is a downstream target of protein kinase B and may be involved in regulation of effects of protein kinase B on thymidine incorporation in FDCP2 cells.''; PubMedEurope PMCScholia
Wijkander J, Landström TR, Manganiello V, Belfrage P, Degerman E.; ''Insulin-induced phosphorylation and activation of phosphodiesterase 3B in rat adipocytes: possible role for protein kinase B but not mitogen-activated protein kinase or p70 S6 kinase.''; PubMedEurope PMCScholia
Du K, Herzig S, Kulkarni RN, Montminy M.; ''TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver.''; PubMedEurope PMCScholia
Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P.; ''Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha.''; PubMedEurope PMCScholia
Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P, Coadwell J, Hawkins PT.; ''Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B.''; PubMedEurope PMCScholia
Baer K, Lisinski I, Gompert M, Stuhlmann D, Schmolz K, Klein HW, Al-Hasani H.; ''Activation of a GST-tagged AKT2/PKBbeta.''; PubMedEurope PMCScholia
Degerman E, Ahmad F, Chung YW, Guirguis E, Omar B, Stenson L, Manganiello V.; ''From PDE3B to the regulation of energy homeostasis.''; PubMedEurope PMCScholia
Maira SM, Galetic I, Brazil DP, Kaech S, Ingley E, Thelen M, Hemmings BA.; ''Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane.''; PubMedEurope PMCScholia
Engelman JA, Luo J, Cantley LC.; ''The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism.''; PubMedEurope PMCScholia
Currie RA, Walker KS, Gray A, Deak M, Casamayor A, Downes CP, Cohen P, Alessi DR, Lucocq J.; ''Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1.''; PubMedEurope PMCScholia
DiPilato LM, Ahmad F, Harms M, Seale P, Manganiello V, Birnbaum MJ.; ''The Role of PDE3B Phosphorylation in the Inhibition of Lipolysis by Insulin.''; PubMedEurope PMCScholia
Degerman E, Belfrage P, Manganiello VC.; ''Structure, localization, and regulation of cGMP-inhibited phosphodiesterase (PDE3).''; PubMedEurope PMCScholia
Kooijman R, Lauf JJ, Kappers AC, Rijkers GT.; ''Insulin-like growth factor induces phosphorylation of immunoreactive insulin receptor substrate and its association with phosphatidylinositol-3 kinase in human thymocytes.''; PubMedEurope PMCScholia
Burke JE, Vadas O, Berndt A, Finegan T, Perisic O, Williams RL.; ''Dynamics of the phosphoinositide 3-kinase p110δ interaction with p85α and membranes reveals aspects of regulation distinct from p110α.''; PubMedEurope PMCScholia
Manganiello VC, Taira M, Degerman E, Belfrage P.; ''Type III cGMP-inhibited cyclic nucleotide phosphodiesterases (PDE3 gene family).''; PubMedEurope PMCScholia
Mandelker D, Gabelli SB, Schmidt-Kittler O, Zhu J, Cheong I, Huang CH, Kinzler KW, Vogelstein B, Amzel LM.; ''A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane.''; PubMedEurope PMCScholia
Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, Holmes AB, McCormick F, Hawkins PT.; ''Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B.''; PubMedEurope PMCScholia
James SR, Downes CP, Gigg R, Grove SJ, Holmes AB, Alessi DR.; ''Specific binding of the Akt-1 protein kinase to phosphatidylinositol 3,4,5-trisphosphate without subsequent activation.''; PubMedEurope PMCScholia
Liu AX, Testa JR, Hamilton TC, Jove R, Nicosia SV, Cheng JQ.; ''AKT2, a member of the protein kinase B family, is activated by growth factors, v-Ha-ras, and v-src through phosphatidylinositol 3-kinase in human ovarian epithelial cancer cells.''; PubMedEurope PMCScholia
Interleukins are low molecular weight proteins that bind to cell surface receptors and act in an autocrine and/or paracrine fashion. They were first identified as factors produced by leukocytes but are now known to be produced by many other cells throughout the body. They have pleiotropic effects on cells which bind them, impacting processes such as tissue growth and repair, hematopoietic homeostasis, and multiple levels of the host defense against pathogens where they are an essential part of the immune system.
While the existence of a "b" isoform of fibroblast growth factor receptor 1 is well established and its biochemical and functional properties have been extensively characterized (e.g., Mohammadi et al. 2005; Zhang et al. 2006), its amino acid sequence is not represented in reference protein sequence databases, except as the 47-residue polypeptide (deposited in GenBank as accession AAB19502) first used by Johnson et al. (1991) to distinguish the "b" and "c" isoforms of the receptor.
PI3K can be activated downstream of receptor tyrosine kinases (RTKs) such as insulin receptor IGF1R (Hadari et al. 1992, Kooijman et al. 1995). 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, facilitating phosphorylation (Mandelker et al. 2009, Burke et al. 2011; reviewed in Koyasu et al, 2003; Engelman et al, 2006).
The phosphorylation of membrane-recruited AKT at threonine and serine can be inhibited by direct binding of two different proteins, C-terminal modulator protein (THEM4 i.e. CTMP), which binds to the carboxy-terminal tail of AKT (Maira et al. 2001), or Tribbles homolog 3 (TRIB3), which binds to the catalytic domain of AKT (Du et al. 2003).
PIP3 generated by PI3K recruits phosphatidylinositide-dependent protein kinase 1 (PDPK1 i.e. PDK1) to the membrane, through its PH (pleckstrin-homology) domain. PDPK1 binds PIP3 with high affinity, and also shows low affinity for PIP2 (Currie et al. 1999; Anderson et al, 1998).
Two specific sites in AKT2, one in the kinase domain (Thr-309) and the other in the C-terminal regulatory region (Ser-474), need to be phosphorylated for its full activation.
Based on work done in mouse with AKT1, AKT2 is predicted to phosphorylate PDE3B downstream of insulin signaling (Wijknader et al, 1998; Kitamura et al, 1999; Ahmad et al, 2000; reviewed in Degerman et al, 2011).
PDE3B hydrolyzes cAMP to AMP downstream of insulin signaling to regulate energy homeostasis (Marganiello et al, 1995; Degerman et al, 1997; Degerman et al, 2011; DiPilato et al, 2015).
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
Annotated Interactions