Immune response - PIP3 signaling in B lymphocytes

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PIP3 signaling in B lymphocytes

B lymphocytes play a critical role in the regulation of numerous cellular processes, such as proliferation, differentiation, chemotaxis, glucose homeostasis and others. B cell antigen receptor (BCR) engagement triggers a cascade of biochemical events that culminate in B cell activation, which entails the proliferation and differentiation of B cells.

The efficient and coordinated generation of a number of second messengers, including IP3 (inositol-1,4,5-trisphosphate), DAG (diacylglycerol), PI(3,4)P2 (phosphatidylinositol-3,4-biphosphate) and PI(3,4,5)P3 (phosphatidylinositol-3,4,5-trisphosphate), is required for normal B cell function.

The BCR is a multiprotein complex that is composed of mIg molecules (Membrane Immunoglobulin) and associated Ig-Alpha(CD79A)/Ig-Beta(CD79B) heterodimer [1]. The mIg subunits bind antigen and cause receptor aggregation, while the CD79A/ CD79B subunits transduce signals to the cell interior. Engagement of receptor activates intracellular protein tyrosine kinases Syk and Lyn, which phosphorylate and activate numerous signal proteins, including phosphoinositide-3-kinase adaptor protein (PI3KAP1) [2], Bruton tyrosine kinase (BTK) [3], and co-receptor CD19 [4].

Transmembrane receptor CD45 has its own protein tyrosine phosphatase activity. CD45 inhibits Lyn activity by dephosphorylation [5]. BCR signals somehow reduce CD45's negative regulatory effects by inducing phosphorylation of Lyn [6].

CD19 is a cell surface molecule, which assembles with the BCR in order to decrease the threshold for antigen receptor-dependent stimulation. Lyn phosphorylates and activates CD19, which in turn binds to Vav1 and induces Rac1 signaling cascade [7]. Rac1 activates phosphatidylinositol 3-kinase class1A via binding to its regulatory subunit (PI3KR class1A) [8]. CD19 can directly bind to PI3KR class1A, recruiting PI3K to the plasma membrane for increasing the specific activity of the enzyme. Adaptor PI3KAP1 also recruits PI3K to the plasma membrane [2].

The class IB of phosphatidylinositol 3-kinase (PI3K class 1B) is activated by G beta/gamma proteins on stimulation of G protein-coupled receptors (GPCRs). G beta/gamma proteins mediate membrane recruitment of its regulatory subunit (PI3KR class 1B), and direct stimulation of its catalytic subunit (PI3KC class 1B) [9].

Activated PI3K phosphorylates the membrane lipid phosphatidylinositol 4,5-biphosphate (PI(4,5)P2) to phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3) [10]. PI(3,4,5)P3 is the second messenger that activates PDK and AKT [10], [11].

Phosphatase PTEN acts as a negative regulator for the PI3K/AKT signaling pathway, converting PI(3,4,5)P3 into PI(4,5)P2 [12].

Upon phosphorylation by Lyn, Fc-gamma-RIIb1 activates phosphatase SHIP1. SHIP1 converts PI(3,4,5)P3 into PI(3,4)P2, which is the second messenger that activates PDK and AKT [11].

BTK is required for B cell development and BCR function. Cross-linking of BCR induces phosphorylation of BTK by Lyn [13]. BTK activates both phospholipase isoforms PLC-gamma-1 and PLC-gamma-2 [3], [4].

Phospholipase PLC-beta is activated by G-proteins, such as G beta/gamma. Phospholipases PLC-beta and -gamma catalyze the hydrolysis of PI(4,5)P2 to form IP3 and DAG. IP3, being released into the cytoplasm, binds to IP3R (IP3 Receptor) on the surface of Endoplasmic Reticulum and mobilizes Ca(II) from internal stores [14].

References:

  1. Geisberger R, Crameri R, Achatz G
    Models of signal transduction through the B-cell antigen receptor. Immunology 2003 Dec;110(4):401-10
  2. Okada T, Maeda A, Iwamatsu A, Gotoh K, Kurosaki T
    BCAP: the tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation. Immunity 2000 Dec;13(6):817-27
  3. Mohamed AJ, Nore BF, Christensson B, Smith CI
    Signalling of Bruton's tyrosine kinase, Btk. Scandinavian journal of immunology 1999 Feb;49(2):113-8
  4. Pao LI, Cambier JC
    Syk, but not Lyn, recruitment to B cell antigen receptor and activation following stimulation of CD45- B cells. Journal of immunology (Baltimore, Md. : 1950) 1997 Mar 15;158(6):2663-9
  5. Harashima A, Suzuki M, Okochi A, Yamamoto M, Matsuo Y, Motoda R, Yoshioka T, Orita K
    CD45 tyrosine phosphatase inhibits erythroid differentiation of umbilical cord blood CD34+ cells associated with selective inactivation of Lyn. Blood 2002 Dec 15;100(13):4440-5
  6. Shrivastava P, Katagiri T, Ogimoto M, Mizuno K, Yakura H
    Dynamic regulation of Src-family kinases by CD45 in B cells. Blood 2004 Feb 15;103(4):1425-32
  7. O'Rourke LM, Tooze R, Turner M, Sandoval DM, Carter RH, Tybulewicz VL, Fearon DT
    CD19 as a membrane-anchored adaptor protein of B lymphocytes: costimulation of lipid and protein kinases by recruitment of Vav. Immunity 1998 May;8(5):635-45
  8. Djouder N, Schmidt G, Frings M, Cavalié A, Thelen M, Aktories K
    Rac and phosphatidylinositol 3-kinase regulate the protein kinase B in Fc epsilon RI signaling in RBL 2H3 mast cells. Journal of immunology (Baltimore, Md. : 1950) 2001 Feb 1;166(3):1627-34
  9. Brock C, Schaefer M, Reusch HP, Czupalla C, Michalke M, Spicher K, Schultz G, Nürnberg B
    Roles of G beta gamma in membrane recruitment and activation of p110 gamma/p101 phosphoinositide 3-kinase gamma. The Journal of cell biology 2003 Jan 6;160(1):89-99
  10. 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
  11. Lemmon MA
    Phosphoinositide recognition domains. Traffic (Copenhagen, Denmark) 2003 Apr;4(4):201-13
  12. 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
  13. Kurosaki T, Kurosaki M
    Transphosphorylation of Bruton's tyrosine kinase on tyrosine 551 is critical for B cell antigen receptor function. The Journal of biological chemistry 1997 Jun 20;272(25):15595-8
  14. Katan M
    The control of inositol lipid hydrolysis. Cancer surveys 1996;27:199-211

  1. Geisberger R, Crameri R, Achatz G
    Models of signal transduction through the B-cell antigen receptor. Immunology 2003 Dec;110(4):401-10
  2. Okada T, Maeda A, Iwamatsu A, Gotoh K, Kurosaki T
    BCAP: the tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation. Immunity 2000 Dec;13(6):817-27
  3. Mohamed AJ, Nore BF, Christensson B, Smith CI
    Signalling of Bruton's tyrosine kinase, Btk. Scandinavian journal of immunology 1999 Feb;49(2):113-8
  4. Pao LI, Cambier JC
    Syk, but not Lyn, recruitment to B cell antigen receptor and activation following stimulation of CD45- B cells. Journal of immunology (Baltimore, Md. : 1950) 1997 Mar 15;158(6):2663-9
  5. Harashima A, Suzuki M, Okochi A, Yamamoto M, Matsuo Y, Motoda R, Yoshioka T, Orita K
    CD45 tyrosine phosphatase inhibits erythroid differentiation of umbilical cord blood CD34+ cells associated with selective inactivation of Lyn. Blood 2002 Dec 15;100(13):4440-5
  6. Shrivastava P, Katagiri T, Ogimoto M, Mizuno K, Yakura H
    Dynamic regulation of Src-family kinases by CD45 in B cells. Blood 2004 Feb 15;103(4):1425-32
  7. O'Rourke LM, Tooze R, Turner M, Sandoval DM, Carter RH, Tybulewicz VL, Fearon DT
    CD19 as a membrane-anchored adaptor protein of B lymphocytes: costimulation of lipid and protein kinases by recruitment of Vav. Immunity 1998 May;8(5):635-45
  8. Djouder N, Schmidt G, Frings M, Cavalié A, Thelen M, Aktories K
    Rac and phosphatidylinositol 3-kinase regulate the protein kinase B in Fc epsilon RI signaling in RBL 2H3 mast cells. Journal of immunology (Baltimore, Md. : 1950) 2001 Feb 1;166(3):1627-34
  9. Brock C, Schaefer M, Reusch HP, Czupalla C, Michalke M, Spicher K, Schultz G, Nürnberg B
    Roles of G beta gamma in membrane recruitment and activation of p110 gamma/p101 phosphoinositide 3-kinase gamma. The Journal of cell biology 2003 Jan 6;160(1):89-99
  10. 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
  11. Lemmon MA
    Phosphoinositide recognition domains. Traffic (Copenhagen, Denmark) 2003 Apr;4(4):201-13
  12. 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
  13. Kurosaki T, Kurosaki M
    Transphosphorylation of Bruton's tyrosine kinase on tyrosine 551 is critical for B cell antigen receptor function. The Journal of biological chemistry 1997 Jun 20;272(25):15595-8
  14. Katan M
    The control of inositol lipid hydrolysis. Cancer surveys 1996;27:199-211

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