Ror2/Frizzled Complex Mediates Wnt5a-induced AP-1 Activation by Regulating Dishevelled Polymerization

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2010 May 12

PMID 20457807

Citations 93

Authors

Michiru Nishita

Sumiyo Itsukushima

Akira Nomachi

Mitsuharu Endo

Zhichao Wang

Daisuke Inaba

Sen Qiao

Shinji Takada

Akira Kikuchi

Yasuhiro Minami

Affiliations

Soon will be listed here.

Abstract

The receptor tyrosine kinase Ror2 acts as a receptor or coreceptor for Wnt5a to mediate Wnt5a-induced activation of the Wnt/JNK pathway and inhibition of the beta-catenin-dependent canonical Wnt pathway. However, little is known about how Ror2 cooperates with another receptor component(s) to mediate Wnt5a signaling. We show here that Ror2 regulates Wnt5a-induced polymerization of Dishevelled (Dvl) and that this Ror2-mediated regulation of Dvl is independent of the cytoplasmic region of Ror2. Ror2 can associate with Frizzled7 (Fz7) via its extracellular cysteine-rich domain to form a receptor complex that is required for the regulation of Dvl and activation of the AP-1 promoter after Wnt5a stimulation. Suppressed expression of Fz7 indeed results in the inhibition of Wnt5a-induced polymerization of Dvl and AP-1 activation. Interestingly, both the DIX and the DEP domains of Dvl are indispensable for Dvl polymerization and subsequent AP-1 activation after Wnt5a stimulation. We further show that polymerized Dvl is colocalized with Rac1 and that suppressed expression of Rac1 inhibits Wnt5a-induced AP-1 activation. Collectively, our results indicate that Ror2/Fz receptor complex plays an important role in the Wnt5a/Rac1/AP-1 pathway by regulating the polymerization of Dvl.

Citing Articles

Wnt/β-Catenin Signaling and Congenital Abnormalities of Kidney and Urinary Tract.

Yu C, Zheng B, Zhang L, Zhang A, Jia Z, Ding G Kidney Dis (Basel). 2024; 10(6):588-599.

PMID: 39664338 PMC: 11631108. DOI: 10.1159/000541684.

Wnt signalosomes: What we know that we do not know.

Hartmann H, Siddiqui G, Bryant J, Robbins D, Weiss V, Ahmed Y Bioessays. 2024; 47(2):e2400110.

PMID: 39520379 PMC: 11755710. DOI: 10.1002/bies.202400110.

Ror2 signaling regulated by differential Wnt proteins determines pathological fate of muscle mesenchymal progenitors.

Kamizaki K, Katsukawa M, Yamamoto A, Fukada S, Uezumi A, Endo M Cell Death Dis. 2024; 15(10):784.

PMID: 39468010 PMC: 11519583. DOI: 10.1038/s41419-024-07173-9.

Wnt5a and Notum Influence the Temporal Dynamics of Cartilaginous Mesenchymal Condensations in Developing Trachea.

Bottasso-Arias N, Mohanakrishnan M, Trovillion S, Burra K, Russell N, Wu Y bioRxiv. 2024; .

PMID: 39282283 PMC: 11398369. DOI: 10.1101/2024.09.02.610014.

Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and disease.

Hu L, Chen W, Qian A, Li Y Bone Res. 2024; 12(1):39.

PMID: 38987555 PMC: 11237130. DOI: 10.1038/s41413-024-00342-8.

References

Matsuda T, Nomi M, Ikeya M, Kani S, Oishi I, Terashima T . Expression of the receptor tyrosine kinase genes, Ror1 and Ror2, during mouse development. Mech Dev. 2001; 105(1-2):153-6. DOI: 10.1016/s0925-4773(01)00383-5. View

Perrimon N, Mahowald A . Multiple functions of segment polarity genes in Drosophila. Dev Biol. 1987; 119(2):587-600. DOI: 10.1016/0012-1606(87)90061-3. View

MacDonald B, Tamai K, He X . Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009; 17(1):9-26. PMC: 2861485. DOI: 10.1016/j.devcel.2009.06.016. View

Nishita M, Yoo S, Nomachi A, Kani S, Sougawa N, Ohta Y . Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration. J Cell Biol. 2006; 175(4):555-62. PMC: 2064592. DOI: 10.1083/jcb.200607127. View

Matsuda T, Suzuki H, Oishi I, Kani S, Kuroda Y, Komori T . The receptor tyrosine kinase Ror2 associates with the melanoma-associated antigen (MAGE) family protein Dlxin-1 and regulates its intracellular distribution. J Biol Chem. 2003; 278(31):29057-64. DOI: 10.1074/jbc.M302199200. View

Yamamoto S, Nishimura O, Misaki K, Nishita M, Minami Y, Yonemura S . Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex. Dev Cell. 2008; 15(1):23-36. DOI: 10.1016/j.devcel.2008.05.007. View

Kani S, Oishi I, Yamamoto H, Yoda A, Suzuki H, Nomachi A . The receptor tyrosine kinase Ror2 associates with and is activated by casein kinase Iepsilon. J Biol Chem. 2004; 279(48):50102-9. DOI: 10.1074/jbc.M409039200. View

Yoon Y, McNiven M . Mitochondrial division: New partners in membrane pinching. Curr Biol. 2001; 11(2):R67-70. DOI: 10.1016/s0960-9822(01)00011-2. View

Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B . The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells. 2003; 8(7):645-54. DOI: 10.1046/j.1365-2443.2003.00662.x. View

10.

Axelrod J, Miller J, Shulman J, Moon R, Perrimon N . Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways. Genes Dev. 1998; 12(16):2610-22. PMC: 317102. DOI: 10.1101/gad.12.16.2610. View

11.

Wiederkehr A, Avaro S, Haguenauer-Tsapis R, Riezman H . The F-box protein Rcy1p is involved in endocytic membrane traffic and recycling out of an early endosome in Saccharomyces cerevisiae. J Cell Biol. 2000; 149(2):397-410. PMC: 2175155. DOI: 10.1083/jcb.149.2.397. View

12.

Smalley M, Signoret N, Robertson D, Tilley A, Hann A, Ewan K . Dishevelled (Dvl-2) activates canonical Wnt signalling in the absence of cytoplasmic puncta. J Cell Sci. 2005; 118(Pt 22):5279-89. DOI: 10.1242/jcs.02647. View

13.

Witte F, Bernatik O, Kirchner K, Masek J, Mahl A, Krejci P . Negative regulation of Wnt signaling mediated by CK1-phosphorylated Dishevelled via Ror2. FASEB J. 2010; 24(7):2417-26. DOI: 10.1096/fj.09-150615. View

14.

Forrester W, Dell M, Perens E, Garriga G . A C. elegans Ror receptor tyrosine kinase regulates cell motility and asymmetric cell division. Nature. 1999; 400(6747):881-5. DOI: 10.1038/23722. View

15.

OConnell M, Fiori J, Xu M, Carter A, Frank B, Camilli T . The orphan tyrosine kinase receptor, ROR2, mediates Wnt5A signaling in metastatic melanoma. Oncogene. 2009; 29(1):34-44. PMC: 2803338. DOI: 10.1038/onc.2009.305. View

16.

Angers S, Moon R . Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol. 2009; 10(7):468-77. DOI: 10.1038/nrm2717. View

17.

Enomoto M, Hayakawa S, Itsukushima S, Ren D, Matsuo M, Tamada K . Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling. Oncogene. 2009; 28(36):3197-208. DOI: 10.1038/onc.2009.175. View

18.

Schlunck G, Damke H, Kiosses W, Rusk N, Symons M, Waterman-Storer C . Modulation of Rac localization and function by dynamin. Mol Biol Cell. 2003; 15(1):256-67. PMC: 307545. DOI: 10.1091/mbc.e03-01-0019. View

19.

Green J, Inoue T, Sternberg P . Opposing Wnt pathways orient cell polarity during organogenesis. Cell. 2008; 134(4):646-56. PMC: 2603076. DOI: 10.1016/j.cell.2008.06.026. View

20.

Kaykas A, Yang-Snyder J, Heroux M, Shah K, Bouvier M, Moon R . Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization. Nat Cell Biol. 2003; 6(1):52-8. DOI: 10.1038/ncb1081. View