Development - TGF-beta receptor signaling

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TGF-beta receptor signaling

Transforming growth factor beta (TGF-beta) signaling controls diverse cellular processes, including cell proliferation, differentiation, adhesion and migration [1], [2], [3].

TGF-beta 1 initiates signaling by binding to and bringing together type I and type II receptor serine/threonine kinases (TGF-beta receptor type I and II) on the cell surface. This allows TGF-beta receptor type II to phosphorylate the TGF-beta receptor type I kinase domain. TGF-beta receptor type I then propagates the signal through phosphorylation of the SMAD family member (SMAD) proteins [2], [3]. The recognition of SMADs by TGF-beta receptor type I may be facilitated by auxiliary protein Zinc finger FYVE domain containing 9 (SARA) [2]. SMAD2 and SMAD3 proteins form hetero-oligomeric complexes with SMAD4. These SMAD2/SMAD4 and SMAD3/SMAD4 complexes translocate to the nucleus and, depending on the cell type and their interactions with coactivators or corepressors, function as transcriptional modulators [3], [4]. SMAD3 translocation to the nucleus depends on binding of Importin (karyopherin)-beta [5]. Transcription mediated by SMAD2 or SMAD3 is enhanced by CREB binding protein (CBP)/E1A binding protein p300 (p300) [6], [7]. SMADs can bind DNA directly with low affinity and specificity and thus rely on interactions with other DNA-binding proteins to target specific genes for transcriptional regulation, for example Forkhead box H1 (FAST-1/2) [8]. V-ski sarcoma viral oncogene homolog (Ski) and SKI-like oncogene (SnoN) modulate the nuclear activity of SMAD and function as corepressors antagonize TGF-beta signaling [4], [8]. SMAD3-mediated Anaphase-promoting complex with Fizzy/cell division cycle 20 related 1 (APC/hCDH1 complex) activation leads to degradation of SnoN [9]. YY1 transcription factor (YY1) as a SMAD-interacting negatively regulates TGF-beta signaling [10]. TSC22 domain family member 1 (TSC-22) as a SMAD4-interacting positively regulates TGF-beta-dependent erythroid cell differentiation [11].

SMAD7 inhibits TGF-beta receptor type I [3] via competition with SMAD3 or SMAD2 for binding. SMAD7 interaction leads to the ubiquitination and degradation of the receptors with the help SMAD specific E3 ubiquitin protein ligase (SMURF). TGF-beta/SMAD7/SMURF complex is routed via Caveolin-rich membrane structures and internalized via Caveolin-positive vesicles toward the proteasome for degradation. FK506 binding protein 1A 12kDa (FKBP12) inhibits TGF-beta signaling by binding to the unphosphorylated GS regions of TGF-beta receptor type I. This interaction locks the kinase catalytic center of the TGF-beta receptor type I in an unproductive conformation [2], [4]. TGF-beta induces transcription of the human SMAD7 gene through activation of SMAD3 [12], and transcription factor Ets variant gene 1 (ER81) [13]. Kruppel-like factor 10 (TIEG) represses SMAD7 gene [14].

SMADs functionally cooperate with Sp1 transcription factor (SP1) to activate the Cyclin-dependent kinase inhibitor 1A (p21) promoter [15], Cyclin-dependent kinase inhibitor 2B (p15) [16] (cell cycle regulation [17]), Serpin peptidase inhibitor clade E member 1 (PAI1) [18] (regulation of extracellular matrix [17]).

TGF-beta 1 activates p38 MAPK via Mitogen-activated protein kinase kinase kinase 7 interacting protein 1 (TAB1) [19] or SMAD7 [20]/ Mitogen-activated protein kinase kinase kinase 7 (TAK1(MAP3K7))/ Mitogen-activated protein kinase kinase 3 (MEK3(MAP2K3)). TGF-beta 1 activates, via SMAD3 and SMAD4, expression of Growth arrest and DNA-damage-inducible beta (GADD45 beta) that, possibly via Mitogen-activated protein kinase kinase kinase 4 (MEKK4(MAP3K4)) activates Mitogen-activated protein kinase kinase 6 (MEK6(MAP2K6)) and then p38 MAPK [21]. TGF-beta activates, in p38 MAPK-dependent manner, Antigen identified by monoclonal antibody AJ9 (MSK1) activation [22], which is known to phosphorylate TGF-inducible ER81 [13], [23]. ER81 controls SMAD7 expression and V-erb-b2 erythroblastic leukemia viral oncogene homolog 2 neuro/glioblastoma derived oncogene homolog (ErbB2), which is also involved in SMAD7 expression regulation [13].

TGF-beta receptor directly bind SHC transforming protein 1 (Shc) and via possibly V-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras)/ V-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2) activates Mitogen-activated protein kinase 3 and 1 (ERK1/2). This can lead for example to epithelial-to-mesenchymal transition [24], [25], [26]. ERK activates ELK1 member of ETS oncogene family (Elk-1). Elk-1 transcriptionally activates p15 expression [27].

TGF-beta 1 via TAK1(MAP3K7)/ Nuclear factor NFkappaB inhibitor kinases (IKK) inhibition of Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (NFKBIA) activate Nuclear factor kappa B (NF-kB). As a result of NF-kB activation, NFKBIA mRNA and protein levels are increased leading to post-repression of NF-kB and induction of cell death [28]. TSC-22 stimulates apoptosis too [29], [30].

References:

  1. Wrana JL, Attisano L, Wieser R, Ventura F, Massague J
    Mechanism of activation of the TGF-beta receptor. Nature 1994 Aug 4;370(6488):341-7
  2. Shi Y, Massague J
    Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003 Jun 13;113(6):685-700
  3. Bachman KE, Park BH
    Duel nature of TGF-beta signaling: tumor suppressor vs. tumor promoter. Current opinion in oncology 2005 Jan;17(1):49-54
  4. Moustakas A, Souchelnytskyi S, Heldin CH
    Smad regulation in TGF-beta signal transduction. Journal of cell science 2001 Dec;114(Pt 24):4359-69
  5. Kurisaki A, Kose S, Yoneda Y, Heldin CH, Moustakas A
    Transforming growth factor-beta induces nuclear import of Smad3 in an importin-beta1 and Ran-dependent manner. Molecular biology of the cell 2001 Apr;12(4):1079-91
  6. Janknecht R, Wells NJ, Hunter T
    TGF-beta-stimulated cooperation of smad proteins with the coactivators CBP/p300. Genes & development 1998 Jul 15;12(14):2114-9
  7. Tu AW, Luo K
    Acetylation of Smad2 by the co-activator p300 regulates activin and transforming growth factor beta response. The Journal of biological chemistry 2007 Jul 20;282(29):21187-96
  8. Wrana JL
    Regulation of Smad activity. Cell 2000 Jan 21;100(2):189-92
  9. Wan Y, Liu X, Kirschner MW
    The anaphase-promoting complex mediates TGF-beta signaling by targeting SnoN for destruction. Molecular cell 2001 Nov;8(5):1027-39
  10. Kurisaki K, Kurisaki A, Valcourt U, Terentiev AA, Pardali K, Ten Dijke P, Heldin CH, Ericsson J, Moustakas A
    Nuclear factor YY1 inhibits transforming growth factor beta- and bone morphogenetic protein-induced cell differentiation. Molecular and cellular biology 2003 Jul;23(13):4494-510
  11. Choi SJ, Moon JH, Ahn YW, Ahn JH, Kim DU, Han TH
    Tsc-22 enhances TGF-beta signaling by associating with Smad4 and induces erythroid cell differentiation. Molecular and cellular biochemistry 2005 Mar;271(1-2):23-8
  12. von Gersdorff G, Susztak K, Rezvani F, Bitzer M, Liang D, Bottinger EP
    Smad3 and Smad4 mediate transcriptional activation of the human Smad7 promoter by transforming growth factor beta. The Journal of biological chemistry 2000 Apr 14;275(15):11320-6
  13. Dowdy SC, Mariani A, Janknecht R
    HER2/Neu- and TAK1-mediated up-regulation of the transforming growth factor beta inhibitor Smad7 via the ETS protein ER81. The Journal of biological chemistry 2003 Nov 7;278(45):44377-84
  14. Johnsen SA, Subramaniam M, Janknecht R, Spelsberg TC
    TGFbeta inducible early gene enhances TGFbeta/Smad-dependent transcriptional responses. Oncogene 2002 Aug 22;21(37):5783-90
  15. Pardali K, Kurisaki A, Moren A, ten Dijke P, Kardassis D, Moustakas A
    Role of Smad proteins and transcription factor Sp1 in p21(Waf1/Cip1) regulation by transforming growth factor-beta. The Journal of biological chemistry 2000 Sep 22;275(38):29244-56
  16. Feng XH, Lin X, Derynck R
    Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-beta. The EMBO journal 2000 Oct 2;19(19):5178-93
  17. Massague J, Gomis RR
    The logic of TGFbeta signaling. FEBS letters 2006 May 22;580(12):2811-20
  18. Datta PK, Blake MC, Moses HL
    Regulation of plasminogen activator inhibitor-1 expression by transforming growth factor-beta -induced physical and functional interactions between smads and Sp1. The Journal of biological chemistry 2000 Dec 22;275(51):40014-9
  19. Kim SI, Kwak JH, Zachariah M, He Y, Wang L, Choi ME
    TGF-beta-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-beta1-induced MKK3-p38 MAPK activation and stimulation of type I collagen. American journal of physiology. Renal physiology 2007 May;292(5):F1471-8
  20. Edlund S, Bu S, Schuster N, Aspenstrom P, Heuchel R, Heldin NE, ten Dijke P, Heldin CH, Landstrom M
    Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3. Molecular biology of the cell 2003 Feb;14(2):529-44
  21. Groth S, Schulze M, Kalthoff H, Fandrich F, Ungefroren H
    Adhesion and Rac1-dependent regulation of biglycan gene expression by transforming growth factor-beta. Evidence for oxidative signaling through NADPH oxidase. The Journal of biological chemistry 2005 Sep 30;280(39):33190-9
  22. Abecassis L, Rogier E, Vazquez A, Atfi A, Bourgeade MF
    Evidence for a role of MSK1 in transforming growth factor-beta-mediated responses through p38alpha and Smad signaling pathways. The Journal of biological chemistry 2004 Jul 16;279(29):30474-9
  23. Janknecht R
    Regulation of the ER81 transcription factor and its coactivators by mitogen- and stress-activated protein kinase 1 (MSK1). Oncogene 2003 Feb 6;22(5):746-55
  24. Hayashida T, Poncelet AC, Hubchak SC, Schnaper HW
    TGF-beta1 activates MAP kinase in human mesangial cells: a possible role in collagen expression. Kidney international 1999 Nov;56(5):1710-20
  25. Xie L, Law BK, Chytil AM, Brown KA, Aakre ME, Moses HL
    Activation of the Erk pathway is required for TGF-beta1-induced EMT in vitro. Neoplasia (New York, N.Y.) 2004 Sep-Oct;6(5):603-10
  26. Lee MK, Pardoux C, Hall MC, Lee PS, Warburton D, Qing J, Smith SM, Derynck R
    TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. The EMBO journal 2007 Sep 5;26(17):3957-67
  27. Hu PP, Shen X, Huang D, Liu Y, Counter C, Wang XF
    The MEK pathway is required for stimulation of p21(WAF1/CIP1) by transforming growth factor-beta. The Journal of biological chemistry 1999 Dec 10;274(50):35381-7
  28. Arsura M, Panta GR, Bilyeu JD, Cavin LG, Sovak MA, Oliver AA, Factor V, Heuchel R, Mercurio F, Thorgeirsson SS, Sonenshein GE
    Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation. Oncogene 2003 Jan 23;22(3):412-25
  29. Ohta S, Yanagihara K, Nagata K
    Mechanism of apoptotic cell death of human gastric carcinoma cells mediated by transforming growth factor beta. The Biochemical journal 1997 Jun 15;324 ( Pt 3):777-82
  30. Omotehara F, Uchida D, Hino S, Begum NM, Yoshida H, Sato M, Kawamata H
    In vivo enhancement of chemosensitivity of human salivary gland cancer cells by overexpression of TGF-beta stimulated clone-22. Oncology reports 2000 Jul-Aug;7(4):737-40

  1. Wrana JL, Attisano L, Wieser R, Ventura F, Massague J
    Mechanism of activation of the TGF-beta receptor. Nature 1994 Aug 4;370(6488):341-7
  2. Shi Y, Massague J
    Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003 Jun 13;113(6):685-700
  3. Bachman KE, Park BH
    Duel nature of TGF-beta signaling: tumor suppressor vs. tumor promoter. Current opinion in oncology 2005 Jan;17(1):49-54
  4. Moustakas A, Souchelnytskyi S, Heldin CH
    Smad regulation in TGF-beta signal transduction. Journal of cell science 2001 Dec;114(Pt 24):4359-69
  5. Kurisaki A, Kose S, Yoneda Y, Heldin CH, Moustakas A
    Transforming growth factor-beta induces nuclear import of Smad3 in an importin-beta1 and Ran-dependent manner. Molecular biology of the cell 2001 Apr;12(4):1079-91
  6. Janknecht R, Wells NJ, Hunter T
    TGF-beta-stimulated cooperation of smad proteins with the coactivators CBP/p300. Genes & development 1998 Jul 15;12(14):2114-9
  7. Tu AW, Luo K
    Acetylation of Smad2 by the co-activator p300 regulates activin and transforming growth factor beta response. The Journal of biological chemistry 2007 Jul 20;282(29):21187-96
  8. Wrana JL
    Regulation of Smad activity. Cell 2000 Jan 21;100(2):189-92
  9. Wan Y, Liu X, Kirschner MW
    The anaphase-promoting complex mediates TGF-beta signaling by targeting SnoN for destruction. Molecular cell 2001 Nov;8(5):1027-39
  10. Kurisaki K, Kurisaki A, Valcourt U, Terentiev AA, Pardali K, Ten Dijke P, Heldin CH, Ericsson J, Moustakas A
    Nuclear factor YY1 inhibits transforming growth factor beta- and bone morphogenetic protein-induced cell differentiation. Molecular and cellular biology 2003 Jul;23(13):4494-510
  11. Choi SJ, Moon JH, Ahn YW, Ahn JH, Kim DU, Han TH
    Tsc-22 enhances TGF-beta signaling by associating with Smad4 and induces erythroid cell differentiation. Molecular and cellular biochemistry 2005 Mar;271(1-2):23-8
  12. von Gersdorff G, Susztak K, Rezvani F, Bitzer M, Liang D, Bottinger EP
    Smad3 and Smad4 mediate transcriptional activation of the human Smad7 promoter by transforming growth factor beta. The Journal of biological chemistry 2000 Apr 14;275(15):11320-6
  13. Dowdy SC, Mariani A, Janknecht R
    HER2/Neu- and TAK1-mediated up-regulation of the transforming growth factor beta inhibitor Smad7 via the ETS protein ER81. The Journal of biological chemistry 2003 Nov 7;278(45):44377-84
  14. Johnsen SA, Subramaniam M, Janknecht R, Spelsberg TC
    TGFbeta inducible early gene enhances TGFbeta/Smad-dependent transcriptional responses. Oncogene 2002 Aug 22;21(37):5783-90
  15. Pardali K, Kurisaki A, Moren A, ten Dijke P, Kardassis D, Moustakas A
    Role of Smad proteins and transcription factor Sp1 in p21(Waf1/Cip1) regulation by transforming growth factor-beta. The Journal of biological chemistry 2000 Sep 22;275(38):29244-56
  16. Feng XH, Lin X, Derynck R
    Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-beta. The EMBO journal 2000 Oct 2;19(19):5178-93
  17. Massague J, Gomis RR
    The logic of TGFbeta signaling. FEBS letters 2006 May 22;580(12):2811-20
  18. Datta PK, Blake MC, Moses HL
    Regulation of plasminogen activator inhibitor-1 expression by transforming growth factor-beta -induced physical and functional interactions between smads and Sp1. The Journal of biological chemistry 2000 Dec 22;275(51):40014-9
  19. Kim SI, Kwak JH, Zachariah M, He Y, Wang L, Choi ME
    TGF-beta-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-beta1-induced MKK3-p38 MAPK activation and stimulation of type I collagen. American journal of physiology. Renal physiology 2007 May;292(5):F1471-8
  20. Edlund S, Bu S, Schuster N, Aspenstrom P, Heuchel R, Heldin NE, ten Dijke P, Heldin CH, Landstrom M
    Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3. Molecular biology of the cell 2003 Feb;14(2):529-44
  21. Groth S, Schulze M, Kalthoff H, Fandrich F, Ungefroren H
    Adhesion and Rac1-dependent regulation of biglycan gene expression by transforming growth factor-beta. Evidence for oxidative signaling through NADPH oxidase. The Journal of biological chemistry 2005 Sep 30;280(39):33190-9
  22. Abecassis L, Rogier E, Vazquez A, Atfi A, Bourgeade MF
    Evidence for a role of MSK1 in transforming growth factor-beta-mediated responses through p38alpha and Smad signaling pathways. The Journal of biological chemistry 2004 Jul 16;279(29):30474-9
  23. Janknecht R
    Regulation of the ER81 transcription factor and its coactivators by mitogen- and stress-activated protein kinase 1 (MSK1). Oncogene 2003 Feb 6;22(5):746-55
  24. Hayashida T, Poncelet AC, Hubchak SC, Schnaper HW
    TGF-beta1 activates MAP kinase in human mesangial cells: a possible role in collagen expression. Kidney international 1999 Nov;56(5):1710-20
  25. Xie L, Law BK, Chytil AM, Brown KA, Aakre ME, Moses HL
    Activation of the Erk pathway is required for TGF-beta1-induced EMT in vitro. Neoplasia (New York, N.Y.) 2004 Sep-Oct;6(5):603-10
  26. Lee MK, Pardoux C, Hall MC, Lee PS, Warburton D, Qing J, Smith SM, Derynck R
    TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. The EMBO journal 2007 Sep 5;26(17):3957-67
  27. Hu PP, Shen X, Huang D, Liu Y, Counter C, Wang XF
    The MEK pathway is required for stimulation of p21(WAF1/CIP1) by transforming growth factor-beta. The Journal of biological chemistry 1999 Dec 10;274(50):35381-7
  28. Arsura M, Panta GR, Bilyeu JD, Cavin LG, Sovak MA, Oliver AA, Factor V, Heuchel R, Mercurio F, Thorgeirsson SS, Sonenshein GE
    Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation. Oncogene 2003 Jan 23;22(3):412-25
  29. Ohta S, Yanagihara K, Nagata K
    Mechanism of apoptotic cell death of human gastric carcinoma cells mediated by transforming growth factor beta. The Biochemical journal 1997 Jun 15;324 ( Pt 3):777-82
  30. Omotehara F, Uchida D, Hino S, Begum NM, Yoshida H, Sato M, Kawamata H
    In vivo enhancement of chemosensitivity of human salivary gland cancer cells by overexpression of TGF-beta stimulated clone-22. Oncology reports 2000 Jul-Aug;7(4):737-40

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