Development - WNT5A signaling

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WNT5A signaling

WNT5A is a non-canonical member of WNT family of proteins which controls a number of essential processes in early development. WNT5A acts via the "non-canonical" and, to a smaller degree, "canonical" Wnt signaling pathways [1], [2].

The "non-canonical" pathway involves WNT5A activation of FZD2 and ROR2 [1], [2], [3].

Activated by WNT5A, FZD2 transforms heterotrimeric guanine nucleotide binding protein (G-protein), which dissociates onto G-protein alpha-t2 and G-protein beta/gamma) subunits [4]. Activation of G-protein alpha-t2 leads to PDE6 cat activation (most possibly via G-protein alpha-t2 sequestration of PDE6 reg) [5], [6], [7]. PDE6 cat decreases concentration of Cyclic GMP which leads to the suppression of Protein kinase G1 [8] and activation of IP3R1 on endoplasmic reticulum membrane (probably via removing from IP3R1 inhibitory action of IRAG) [9], [10], [11].

Activation of G-protein beta/gamma, in turn, leads to stimulation of PLC-beta activity, which increases IP3 and 1,2-Diacyglycerol level. IP3 binds to the activated IP3R1 and promotes Ca('2+) release into cytosol [12], [13], [14]. It leads to activation of Ca(2+)-dependent PKC-alpha and promotes neuronal differentiation [14], [15]. Also, increased Ca('2+) levels activate catalytic subunits of Calcineurin A (catalytic) and, subsequently, promote NF-AT1(NFATC2) transcriptional activity [7], [16]. Finally, Ca('2+) activates Calmodulin and CaMK II, which promotes TAK1(MAP3K7) and further NLK activation. NLK phosphorylates transcription factor Tcf(Lef) and, thus, suppresses the canonical WNT pathway [17], [18], [19].

Activation of ROR2 receptor by WNT5A activates PI3K reg class IA (p85) and, subsequently (via unknown Guanine nucleotide exchange factor), CDC42. The activated CDC42 stimulates MKK7 (MAP2K7), most likely via binding to MLK2(MAP3K10), MLK3(MAP3K11), followed by JNK(MAPK8-10) activation. JNK(MAPK8-10) phosphorylates c-Jun and ATF-2 and increases their transcriptional activity, thus stimulating embryonic convergent extension movements [20], [21], [22].

Furthermore, WNT5A-activated ROR2 binds to Filamin A, which is involved in filopodium assembly [23], and can additionally stimulate JNK(MAPK8-10) via connection to MEK4(MAP2K4) and MKK7 (MAP2K7) [24], [25].

WNT5A can also act via the canonical pathway, which involves activation of FZD4, FZD5 receptors and LRP5 co-receptor. The activated FZD4 and FZD5 recruit Dsh to plasma membrane and LRP5 binds and inactivates Axin, which leads to inactivation of GSK3 beta, prevention of Axin binding to Beta-catenin and its stabilization. So, Beta-catenin can bind and stimulate transcriptional activity of Tcf(Lef) [1], [2], [26].



Objects list:

1,2-Diacyglycerol 1,2-Diacyglycerol Compound group
ATF-2 Cyclic AMP-dependent transcription factor ATF-2
Axin Axin Protein group
Beta-catenin Catenin beta-1
CDC42 Cell division control protein 42 homolog
Ca('2+) Chemical IUPAC name calcium(+2) cation
Ca('2+) Chemical IUPAC name calcium(+2) cation
CaMK II CaMK II Complex
Calcineurin A (catalytic) Calcineurin A Protein group
Calmodulin Calmodulin
Cyclic GMP Chemical IUPAC name Guanosine 3',5'-cyclic phosphate
Dsh Dishevelled Protein group
FZD2 Frizzled-2
FZD4 Frizzled-4
FZD5 Frizzled-5
Filamin A Filamin-A
G-protein alpha-t2 Guanine nucleotide-binding protein G(t) subunit alpha-2
G-protein beta/gamma G-protein beta/gamma Group of complexes
GSK3 beta Glycogen synthase kinase-3 beta
IP3 Chemical IUPAC name [(1R,2S,3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-diphosphonooxycyclohexyl] dihydrogen phosphate
IP3R1 Inositol 1,4,5-trisphosphate receptor type 1
IRAG Protein MRVI1
JNK(MAPK8-10) c-Jun N-terminal kinases Protein group
LRP5 Low-density lipoprotein receptor-related protein 5
MEK4(MAP2K4) Dual specificity mitogen-activated protein kinase kinase 4
MKK7 (MAP2K7) Dual specificity mitogen-activated protein kinase kinase 7
MLK2(MAP3K10) Mitogen-activated protein kinase kinase kinase 10
MLK3(MAP3K11) Mitogen-activated protein kinase kinase kinase 11
NF-AT1(NFATC2) Nuclear factor of activated T-cells, cytoplasmic 2
NLK Serine/threonine-protein kinase NLK
PDE6 cat Cyclic GMP-specific phosphodiesterase 6 catalytic subunits Protein group
PDE6 reg PDE6 reg Protein group
PI3K reg class IA (p85) Phosphoinositide-3-kinase, regulatory subunit 1 (alpha) Protein group
PKC-alpha Protein kinase C alpha type
PLC-beta Phospholipase C, beta Protein group
Protein kinase G1 cGMP-dependent protein kinase 1
ROR2 Tyrosine-protein kinase transmembrane receptor ROR2
TAK1(MAP3K7) Mitogen-activated protein kinase kinase kinase 7
Tcf(Lef) Tcf(Lef) Protein group
WNT5A Protein Wnt-5a
c-Jun Transcription factor AP-1

References:

  1. Huelsken J, Behrens J
    The Wnt signalling pathway. Journal of cell science 2002 Nov 1;115(Pt 21):3977-8
  2. Mikels AJ, Nusse R
    Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS biology 2006 Apr;4(4):e115
  3. Minami Y, Oishi I, Endo M, Nishita M
    Ror-family receptor tyrosine kinases in noncanonical Wnt signaling: their implications in developmental morphogenesis and human diseases. Developmental dynamics : an official publication of the American Association of Anatomists 2010 Jan;239(1):1-15
  4. Liu X, Liu T, Slusarski DC, Yang-Snyder J, Malbon CC, Moon RT, Wang H
    Activation of a frizzled-2/beta-adrenergic receptor chimera promotes Wnt signaling and differentiation of mouse F9 teratocarcinoma cells via Galphao and Galphat. Proceedings of the National Academy of Sciences of the United States of America 1999 Dec 7;96(25):14383-8
  5. Ahumada A, Slusarski DC, Liu X, Moon RT, Malbon CC, Wang HY
    Signaling of rat Frizzled-2 through phosphodiesterase and cyclic GMP. Science (New York, N.Y.) 2002 Dec 6;298(5600):2006-10
  6. Fu Y, Yau KW
    Phototransduction in mouse rods and cones. Pflugers Archiv : European journal of physiology 2007 Aug;454(5):805-19
  7. Ma L, Wang HY
    Mitogen-activated protein kinase p38 regulates the Wnt/cyclic GMP/Ca2+ non-canonical pathway. The Journal of biological chemistry 2007 Sep 28;282(39):28980-90
  8. Ma L, Wang HY
    Suppression of cyclic GMP-dependent protein kinase is essential to the Wnt/cGMP/Ca2+ pathway. The Journal of biological chemistry 2006 Oct 13;281(41):30990-1001
  9. Schlossmann J, Ammendola A, Ashman K, Zong X, Huber A, Neubauer G, Wang GX, Allescher HD, Korth M, Wilm M, Hofmann F, Ruth P
    Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Ibeta. Nature 2000 Mar 9;404(6774):197-201
  10. Kühl M
    The WNT/calcium pathway: biochemical mediators, tools and future requirements. Frontiers in bioscience : a journal and virtual library 2004 Jan 1;9:967-74
  11. Geiselhöringer A, Werner M, Sigl K, Smital P, Wörner R, Acheo L, Stieber J, Weinmeister P, Feil R, Feil S, Wegener J, Hofmann F, Schlossmann J
    IRAG is essential for relaxation of receptor-triggered smooth muscle contraction by cGMP kinase. The EMBO journal 2004 Oct 27;23(21):4222-31
  12. Slusarski DC, Corces VG, Moon RT
    Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling. Nature 1997 Nov 27;390(6658):410-3
  13. Wang HY, Malbon CC
    Wnt signaling, Ca2+, and cyclic GMP: visualizing Frizzled functions. Science (New York, N.Y.) 2003 Jun 6;300(5625):1529-30
  14. Yu JM, Kim JH, Song GS, Jung JS
    Increase in proliferation and differentiation of neural progenitor cells isolated from postnatal and adult mice brain by Wnt-3a and Wnt-5a. Molecular and cellular biochemistry 2006 Aug;288(1-2):17-28
  15. Sheldahl LC, Park M, Malbon CC, Moon RT
    Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner. Current biology : CB 1999 Jul 1;9(13):695-8
  16. Saneyoshi T, Kume S, Amasaki Y, Mikoshiba K
    The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos. Nature 2002 May 16;417(6886):295-9
  17. Kühl M, Sheldahl LC, Malbon CC, Moon RT
    Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus. The Journal of biological chemistry 2000 Apr 28;275(17):12701-11
  18. Ishitani T, Kishida S, Hyodo-Miura J, Ueno N, Yasuda J, Waterman M, Shibuya H, Moon RT, Ninomiya-Tsuji J, Matsumoto K
    The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling. Molecular and cellular biology 2003 Jan;23(1):131-9
  19. Wang HY, Malbon CC
    Wnt-frizzled signaling to G-protein-coupled effectors. Cellular and molecular life sciences : CMLS 2004 Jan;61(1):69-75
  20. Yamanaka H, Moriguchi T, Masuyama N, Kusakabe M, Hanafusa H, Takada R, Takada S, Nishida E
    JNK functions in the non-canonical Wnt pathway to regulate convergent extension movements in vertebrates. EMBO reports 2002 Jan;3(1):69-75
  21. Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B, Koshida I, Suzuki K, Yamada G, Schwabe GC, Mundlos S, Shibuya H, Takada S, Minami Y
    The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes to cells : devoted to molecular & cellular mechanisms 2003 Jul;8(7):645-54
  22. Schambony A, Wedlich D
    Wnt-5A/Ror2 regulate expression of XPAPC through an alternative noncanonical signaling pathway. Developmental cell 2007 May;12(5):779-92
  23. Nishita M, Yoo SK, Nomachi A, Kani S, Sougawa N, Ohta Y, Takada S, Kikuchi A, Minami Y
    Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration. The Journal of cell biology 2006 Nov 20;175(4):555-62
  24. Nomachi A, Nishita M, Inaba D, Enomoto M, Hamasaki M, Minami Y
    Receptor tyrosine kinase Ror2 mediates Wnt5a-induced polarized cell migration by activating c-Jun N-terminal kinase via actin-binding protein filamin A. The Journal of biological chemistry 2008 Oct 10;283(41):27973-81
  25. Nakagawa K, Sugahara M, Yamasaki T, Kajiho H, Takahashi S, Hirayama J, Minami Y, Ohta Y, Watanabe T, Hata Y, Katada T, Nishina H
    Filamin associates with stress signalling kinases MKK7 and MKK4 and regulates JNK activation. The Biochemical journal 2010 Mar 29;427(2):237-45
  26. He X, Saint-Jeannet JP, Wang Y, Nathans J, Dawid I, Varmus H
    A member of the Frizzled protein family mediating axis induction by Wnt-5A. Science (New York, N.Y.) 1997 Mar 14;275(5306):1652-4

  1. Huelsken J, Behrens J
    The Wnt signalling pathway. Journal of cell science 2002 Nov 1;115(Pt 21):3977-8
  2. Mikels AJ, Nusse R
    Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS biology 2006 Apr;4(4):e115
  3. Minami Y, Oishi I, Endo M, Nishita M
    Ror-family receptor tyrosine kinases in noncanonical Wnt signaling: their implications in developmental morphogenesis and human diseases. Developmental dynamics : an official publication of the American Association of Anatomists 2010 Jan;239(1):1-15
  4. Liu X, Liu T, Slusarski DC, Yang-Snyder J, Malbon CC, Moon RT, Wang H
    Activation of a frizzled-2/beta-adrenergic receptor chimera promotes Wnt signaling and differentiation of mouse F9 teratocarcinoma cells via Galphao and Galphat. Proceedings of the National Academy of Sciences of the United States of America 1999 Dec 7;96(25):14383-8
  5. Ahumada A, Slusarski DC, Liu X, Moon RT, Malbon CC, Wang HY
    Signaling of rat Frizzled-2 through phosphodiesterase and cyclic GMP. Science (New York, N.Y.) 2002 Dec 6;298(5600):2006-10
  6. Fu Y, Yau KW
    Phototransduction in mouse rods and cones. Pflugers Archiv : European journal of physiology 2007 Aug;454(5):805-19
  7. Ma L, Wang HY
    Mitogen-activated protein kinase p38 regulates the Wnt/cyclic GMP/Ca2+ non-canonical pathway. The Journal of biological chemistry 2007 Sep 28;282(39):28980-90
  8. Ma L, Wang HY
    Suppression of cyclic GMP-dependent protein kinase is essential to the Wnt/cGMP/Ca2+ pathway. The Journal of biological chemistry 2006 Oct 13;281(41):30990-1001
  9. Schlossmann J, Ammendola A, Ashman K, Zong X, Huber A, Neubauer G, Wang GX, Allescher HD, Korth M, Wilm M, Hofmann F, Ruth P
    Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Ibeta. Nature 2000 Mar 9;404(6774):197-201
  10. Kühl M
    The WNT/calcium pathway: biochemical mediators, tools and future requirements. Frontiers in bioscience : a journal and virtual library 2004 Jan 1;9:967-74
  11. Geiselhöringer A, Werner M, Sigl K, Smital P, Wörner R, Acheo L, Stieber J, Weinmeister P, Feil R, Feil S, Wegener J, Hofmann F, Schlossmann J
    IRAG is essential for relaxation of receptor-triggered smooth muscle contraction by cGMP kinase. The EMBO journal 2004 Oct 27;23(21):4222-31
  12. Slusarski DC, Corces VG, Moon RT
    Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling. Nature 1997 Nov 27;390(6658):410-3
  13. Wang HY, Malbon CC
    Wnt signaling, Ca2+, and cyclic GMP: visualizing Frizzled functions. Science (New York, N.Y.) 2003 Jun 6;300(5625):1529-30
  14. Yu JM, Kim JH, Song GS, Jung JS
    Increase in proliferation and differentiation of neural progenitor cells isolated from postnatal and adult mice brain by Wnt-3a and Wnt-5a. Molecular and cellular biochemistry 2006 Aug;288(1-2):17-28
  15. Sheldahl LC, Park M, Malbon CC, Moon RT
    Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner. Current biology : CB 1999 Jul 1;9(13):695-8
  16. Saneyoshi T, Kume S, Amasaki Y, Mikoshiba K
    The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos. Nature 2002 May 16;417(6886):295-9
  17. Kühl M, Sheldahl LC, Malbon CC, Moon RT
    Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus. The Journal of biological chemistry 2000 Apr 28;275(17):12701-11
  18. Ishitani T, Kishida S, Hyodo-Miura J, Ueno N, Yasuda J, Waterman M, Shibuya H, Moon RT, Ninomiya-Tsuji J, Matsumoto K
    The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling. Molecular and cellular biology 2003 Jan;23(1):131-9
  19. Wang HY, Malbon CC
    Wnt-frizzled signaling to G-protein-coupled effectors. Cellular and molecular life sciences : CMLS 2004 Jan;61(1):69-75
  20. Yamanaka H, Moriguchi T, Masuyama N, Kusakabe M, Hanafusa H, Takada R, Takada S, Nishida E
    JNK functions in the non-canonical Wnt pathway to regulate convergent extension movements in vertebrates. EMBO reports 2002 Jan;3(1):69-75
  21. Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B, Koshida I, Suzuki K, Yamada G, Schwabe GC, Mundlos S, Shibuya H, Takada S, Minami Y
    The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes to cells : devoted to molecular & cellular mechanisms 2003 Jul;8(7):645-54
  22. Schambony A, Wedlich D
    Wnt-5A/Ror2 regulate expression of XPAPC through an alternative noncanonical signaling pathway. Developmental cell 2007 May;12(5):779-92
  23. Nishita M, Yoo SK, Nomachi A, Kani S, Sougawa N, Ohta Y, Takada S, Kikuchi A, Minami Y
    Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration. The Journal of cell biology 2006 Nov 20;175(4):555-62
  24. Nomachi A, Nishita M, Inaba D, Enomoto M, Hamasaki M, Minami Y
    Receptor tyrosine kinase Ror2 mediates Wnt5a-induced polarized cell migration by activating c-Jun N-terminal kinase via actin-binding protein filamin A. The Journal of biological chemistry 2008 Oct 10;283(41):27973-81
  25. Nakagawa K, Sugahara M, Yamasaki T, Kajiho H, Takahashi S, Hirayama J, Minami Y, Ohta Y, Watanabe T, Hata Y, Katada T, Nishina H
    Filamin associates with stress signalling kinases MKK7 and MKK4 and regulates JNK activation. The Biochemical journal 2010 Mar 29;427(2):237-45
  26. He X, Saint-Jeannet JP, Wang Y, Nathans J, Dawid I, Varmus H
    A member of the Frizzled protein family mediating axis induction by Wnt-5A. Science (New York, N.Y.) 1997 Mar 14;275(5306):1652-4

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