Signal transduction - PTEN pathway

PTEN pathway

Phosphatase and tensin homolog (PTEN) is a known tumor suppressor. It inhibits growth factor-induced cell proliferation, division and regulates Integrin-mediated cell adhesion and survival [1].

PTEN antagonizes Phosphoinositide-3-kinase (PI3K), dephosphorylating Phosphatidylinositol (3,4,5) (PtdIns(3,4,5)P3) and inhibits V-akt murine thymoma viral oncogene homolog 1 (PI3K)/AKT-mediated signaling pathways [1].As a result, PTEN prevents Insulin-like growth factor 1 (IGF-1) signaling [2], [3] and activation of the Epidermal growth factor receptor (EGFR)-induced FK506 binding protein 12-rapamycin associated protein 1 (mTOR) [4]. PTEN also inhibits Mdm2 p53 binding protein homolog (MDM2) and protects Tumor protein p53 (p53) via PI3K/AKT-dependent as well as via direct binding of p53 thus blocking antiapoptotic processes [5], [6]. Prevention of PI3K/AKT pathway activation by PTEN also increases activity of Glycogen synthase kinase 3 (GSK3). This leads to decrease of Beta-catenin nuclear accumulation and prevents transcription of the Transcription factor 7 (in a complex Tcf(Lef)) and others genes. Thus, PTEN antagonizes Integrin/Integrin-linked kinase (ILK)-mediated nuclear accumulation of Beta-catenin [7]. Inhibition of PI3K/AKT decreases Cyclin-dependent kinase inhibitor 1A (p21)-mediated cell cycle regulation [8]. PTEN-dependent PI3K/AKT inhibition also decreases Caspase 9 apoptosis-related cysteine peptidase (Caspase-9) activity [9], as well as the apoptosis mediated by Forkhead box O3 (FOXO3A)-mediated [10] and BCL2-associated agonist of cell death (BAD) [11].

PTEN dephosphorylates PTK2 protein tyrosine kinase 2 (FAK1) and SHC transforming protein 1 (Shc). This prevents Integrin (for example alpha-5/beta-1 integrin)/FAK1 and Shc/ Growth factor receptor-bound protein 2 (GRB2) [12], [13] and EGF/Shc/GRB2-mediated [12] Mitogen-activated protein kinase 1/3 (ERK1/2) activation. ERK1/2 inhibition prevents cell spreading, migration [12], [13] and growth. Dephosphorylation of FAK1 also disrupts its binding of Paxillin and Breast cancer anti-estrogen resistance 1 (p130CAS) [14].

PTEN binds Membrane associated guanylate kinase WW and PDZ domain containing (MAGI) proteins. This enhances the efficiency of PTEN signaling through the formation of the PTEN/MAGI complexes [15]. Caspase 3 apoptosis-related cysteine peptidase (Caspase-3) cleaves PTEN. This inhibits the PTEN pathway [16].

References:

1. Dahia PL
   PTEN, a unique tumor suppressor gene. Endocrine-related cancer 2000 Jun;7(2):115-29
2. Knobbe CB, Merlo A, Reifenberger G
   Pten signaling in gliomas. Neuro-oncology 2002 Jul;4(3):196-211
3. Lackey J, Barnett J, Davidson L, Batty IH, Leslie NR, Downes CP
   Loss of PTEN selectively desensitizes upstream IGF1 and insulin signaling. Oncogene 2007 Nov 1;26(50):7132-42
4. Mellinghoff IK, Cloughesy TF, Mischel PS
   PTEN-mediated resistance to epidermal growth factor receptor kinase inhibitors. Clinical cancer research : an official journal of the American Association for Cancer Research 2007 Jan 15;13(2 Pt 1):378-81
5. Zhou M, Gu L, Findley HW, Jiang R, Woods WG
   PTEN reverses MDM2-mediated chemotherapy resistance by interacting with p53 in acute lymphoblastic leukemia cells. Cancer research 2003 Oct 1;63(19):6357-62
6. Li L, Ross AH
   Why is PTEN an important tumor suppressor? Journal of cellular biochemistry 2007 Dec 15;102(6):1368-74
7. Persad S, Troussard AA, McPhee TR, Mulholland DJ, Dedhar S
   Tumor suppressor PTEN inhibits nuclear accumulation of beta-catenin and T cell/lymphoid enhancer factor 1-mediated transcriptional activation. The Journal of cell biology 2001 Jun 11;153(6):1161-74
8. Yoo LI, Liu DW, Le Vu S, Bronson RT, Wu H, Yuan J
   Pten deficiency activates distinct downstream signaling pathways in a tissue-specific manner. Cancer research 2006 Feb 15;66(4):1929-39
9. Weng L, Brown J, Eng C
   PTEN induces apoptosis and cell cycle arrest through phosphoinositol-3-kinase/Akt-dependent and -independent pathways. Human molecular genetics 2001 Feb 1;10(3):237-42
10. Yamamura Y, Lee WL, Inoue K, Ida H, Ito Y
    RUNX3 cooperates with FoxO3a to induce apoptosis in gastric cancer cells. The Journal of biological chemistry 2006 Feb 24;281(8):5267-76
11. 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
12. Gu J, Tamura M, Yamada KM
    Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. The Journal of cell biology 1998 Nov 30;143(5):1375-83
13. Gu J, Tamura M, Pankov R, Danen EH, Takino T, Matsumoto K, Yamada KM
    Shc and FAK differentially regulate cell motility and directionality modulated by PTEN. The Journal of cell biology 1999 Jul 26;146(2):389-403
14. Tamura M, Gu J, Danen EH, Takino T, Miyamoto S, Yamada KM
    PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. The Journal of biological chemistry 1999 Jul 16;274(29):20693-703
15. Simpson L, Parsons R
    PTEN: life as a tumor suppressor. Experimental cell research 2001 Mar 10;264(1):29-41
16. Torres J, Rodriguez J, Myers MP, Valiente M, Graves JD, Tonks NK, Pulido R
    Phosphorylation-regulated cleavage of the tumor suppressor PTEN by caspase-3: implications for the control of protein stability and PTEN-protein interactions. The Journal of biological chemistry 2003 Aug 15;278(33):30652-60