Ror2 signaling regulates Golgi structure and transport through IFT20 for tumor invasiveness

Scientific Reports - Tập 7 Số 1
Michiru Nishita1, Seung‐Yeol Park2, Tadashi Nishio1, Koki Kamizaki1, Zhichao Wang1, Kota Tamada3, Toru Takumi3, Ryuju Hashimoto4, Hiroki Otani4, Gregory J. Pazour5, Victor W. Hsu2, Yasuhiro Minami1
1Division of Cell Physiology, Department of Physiology and Cell Biology, Kobe University, Graduate School of Medicine, Kobe, 650-0017, Japan
2Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, and Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
3RIKEN Brain Science Institute, Wako, 351-0198, Japan
4Department of Developmental Biology, Faculty of Medicine, Shimane University, Izumo, 690-8504, Japan
5Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA

Tóm tắt

AbstractSignaling through the Ror2 receptor tyrosine kinase promotes invadopodia formation for tumor invasion. Here, we identify intraflagellar transport 20 (IFT20) as a new target of this signaling in tumors that lack primary cilia, and find that IFT20 mediates the ability of Ror2 signaling to induce the invasiveness of these tumors. We also find that IFT20 regulates the nucleation of Golgi-derived microtubules by affecting the GM130-AKAP450 complex, which promotes Golgi ribbon formation in achieving polarized secretion for cell migration and invasion. Furthermore, IFT20 promotes the efficiency of transport through the Golgi complex. These findings shed new insights into how Ror2 signaling promotes tumor invasiveness, and also advance the understanding of how Golgi structure and transport can be regulated.

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Tài liệu tham khảo

Oishi, I. et al. The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells 8, 645–654 (2003).

Nishita, M. et al. Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration. J Cell Biol 175, 555–562 (2006).

Nomachi, A. et al. Receptor Tyrosine Kinase Ror2 Mediates Wnt5a-induced Polarized Cell Migration by Activating c-Jun N-terminal Kinase via Actin-binding Protein Filamin A. J Biol Chem 283, 27973–27981 (2008).

Enomoto, M. et al. Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling. Oncogene 28, 3197–3208 (2009).

Nishita, M. et al. Ror2/Frizzled complex mediates Wnt5a-induced AP-1 activation by regulating Dishevelled polymerization. Mol Cell Biol 30, 3610–3619 (2010).

Yamagata, K. et al. Dissection of Wnt5a-Ror2 Signaling Leading to Matrix Metalloproteinase (MMP-13) Expression. J Biol Chem 287, 1588–1599 (2012).

O’Connell, M. P. et al. Wnt5A activates the calpain-mediated cleavage of filamin A. J Invest Dermatol 129, 1782–1789 (2009).

Akbarzadeh, S. et al. The deleted in brachydactyly B domain of ROR2 is required for receptor activation by recruitment of Src. PLoS ONE 3, e1873 (2008).

Witte, F. et al. Negative regulation of Wnt signaling mediated by CK1-phosphorylated Dishevelled via Ror2. FASEB J. 24, 2417–2426 (2010).

Mikels, A. J. & Nusse, R. Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biol 4, e115 (2006).

Angers, S. & Moon, R. T. Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol 10, 468–477 (2009).

van Amerongen, R. & Nusse, R. Towards an integrated view of Wnt signaling in development. Development 136, 3205–3214 (2009).

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. Dev Dyn 239, 1–15 (2010).

Endo, M., Nishita, M., Fujii, M. & Minami, Y. Insight into the role of wnt5a-induced signaling in normal and cancer cells. Int Rev Cell Mol Biol 314, 117–148 (2015).

Nishita, M., Enomoto, M., Yamagata, K. & Minami, Y. Cell/tissue-tropic functions of Wnt5a signaling in normal and cancer cells. Trends Cell Biol 20, 346–354 (2010).

Ren, D., Minami, Y. & Nishita, M. Critical role of Wnt5a-Ror2 signaling in motility and invasiveness of carcinoma cells following Snail-mediated epithelial-mesenchymal transition. Genes Cells 16, 304–315 (2011).

Fromigue, O., Hamidouche, Z. & Marie, P. J. Blockade of the RhoA-JNK-c-Jun-MMP2 cascade by atorvastatin reduces osteosarcoma cell invasion. J Biol Chem 283, 30549–30556 (2008).

Murphy, D. A. & Courtneidge, S. A. The ‘ins’ and ‘outs’ of podosomes and invadopodia: characteristics, formation and function. Nat Rev Mol Cell Biol 12, 413–426 (2011).

Hoshino, D., Branch, K. M. & Weaver, A. M. Signaling inputs to invadopodia and podosomes. J Cell Sci 126, 2979–2989 (2013).

Wei, J. H. & Seemann, J. Unraveling the Golgi ribbon. Traffic 11, 1391–1400 (2010).

Sutterlin, C. & Colanzi, A. The Golgi and the centrosome: building a functional partnership. J Cell Biol 188, 621–628 (2010).

Yadav, S. & Linstedt, A. D. Golgi positioning. Cold Spring Harb Perspect Biol 3, doi:10.1101/cshperspect.a005322 (2011).

Rogalski, A. A. & Singer, S. J. Associations of elements of the Golgi apparatus with microtubules. J Cell Biol 99, 1092–1100 (1984).

Wehland, J., Henkart, M., Klausner, R. & Sandoval, I. V. Role of microtubules in the distribution of the Golgi apparatus: effect of taxol and microinjected anti-alpha-tubulin antibodies. Proc Natl Acad Sci USA 80, 4286–4290 (1983).

Efimov, A. et al. Asymmetric CLASP-dependent nucleation of noncentrosomal microtubules at the trans-Golgi network. Dev Cell 12, 917–930 (2007).

Miller, P. M. et al. Golgi-derived CLASP-dependent microtubules control Golgi organization and polarized trafficking in motile cells. Nat Cell Biol 11, 1069–1080 (2009).

Rivero, S., Cardenas, J., Bornens, M. & Rios, R. M. Microtubule nucleation at the cis-side of the Golgi apparatus requires AKAP450 and GM130. EMBO J 28, 1016–1028 (2009).

Wheatley, D. N. Primary cilia in normal and pathological tissues. Pathobiology 63, 222–238 (1995).

Pazour, G. J. & Witman, G. B. The vertebrate primary cilium is a sensory organelle. Curr Opin Cell Biol 15, 105–110 (2003).

Rosenbaum, J. L. & Witman, G. B. Intraflagellar transport. Nat Rev Mol Cell Biol 3, 813–825 (2002).

Follit, J. A., Tuft, R. A., Fogarty, K. E. & Pazour, G. J. The intraflagellar transport protein IFT20 is associated with the Golgi complex and is required for cilia assembly. Mol Biol Cell 17, 3781–3792 (2006).

Follit, J. A. et al. The Golgin GMAP210/TRIP11 anchors IFT20 to the Golgi complex. PLoS Genet 4, e1000315 (2008).

Keady, B. T., Le, Y. Z. & Pazour, G. J. IFT20 is required for opsin trafficking and photoreceptor outer segment development. Mol Biol Cell 22, 921–930 (2011).

Finetti, F. et al. Intraflagellar transport is required for polarized recycling of the TCR/CD3 complex to the immune synapse. Nat Cell Biol 11, 1332–1339 (2009).

Finetti, F. et al. Specific recycling receptors are targeted to the immune synapse by the intraflagellar transport system. J Cell Sci 127, 1924–1937 (2014).

Vivar, O. I. et al. IFT20 controls LAT recruitment to the immune synapse and T-cell activation in vivo. Proc Natl Acad Sci USA 113, 386–391 (2016).

Noda, K., Kitami, M., Kitami, K., Kaku, M. & Komatsu, Y. Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development. Proc Natl Acad Sci USA 113, E2589–2597 (2016).

Caspary, T., Larkins, C. E. & Anderson, K. V. The graded response to Sonic Hedgehog depends on cilia architecture. Dev Cell 12, 767–778 (2007).

Duldulao, N. A., Lee, S. & Sun, Z. Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion. Development 136, 4033–4042 (2009).

Caldieri, G. & Buccione, R. Aiming for invadopodia: organizing polarized delivery at sites of invasion. Trends Cell Biol 20, 64–70 (2010).

Yadav, S., Puri, S. & Linstedt, A. D. A primary role for Golgi positioning in directed secretion, cell polarity, and wound healing. Mol Biol Cell 20, 1728–1736 (2009).

Gundersen, G. G., Kalnoski, M. H. & Bulinski, J. C. Distinct populations of microtubules: tyrosinated and nontyrosinated alpha tubulin are distributed differently in vivo. Cell 38, 779–789 (1984).

Sanders, A. A. & Kaverina, I. Nucleation and Dynamics of Golgi-derived Microtubules. Front Neurosci 9, 431 (2015).

Soderberg, O. et al. Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods 3, 995–1000 (2006).

Trucco, A. et al. Secretory traffic triggers the formation of tubular continuities across Golgi sub-compartments. Nat Cell Biol 6, 1071–1081 (2004).

San Pietro, E. et al. Group IV Phospholipase A(2)alpha Controls the Formation of Inter-Cisternal Continuities Involved in Intra-Golgi Transport. PLoS Biol 7, e1000194 (2009).

Yang, J. S. et al. COPI acts in both vesicular and tubular transport. Nat Cell Biol 13, 996–1003 (2011).

Park, S. Y., Yang, J. S., Schmider, A. B., Soberman, R. J. & Hsu, V. W. Coordinated regulation of bidirectional COPI transport at the Golgi by CDC42. Nature 521, 529–532 (2015).

Castro-Castro, A. et al. Cellular and Molecular Mechanisms of MT1-MMP-Dependent Cancer Cell Invasion. Annu Rev Cell Dev Biol 32, 555-576 (2016).

Poincloux, R., Lizarraga, F. & Chavrier, P. Matrix invasion by tumour cells: a focus on MT1-MMP trafficking to invadopodia. J Cell Sci 122, 3015–3024 (2009).

Frittoli, E., Palamidessi, A., Disanza, A. & Scita, G. Secretory and endo/exocytic trafficking in invadopodia formation: the MT1-MMP paradigm. Eur J Cell Biol 90, 108–114 (2011).

Uekita, T., Itoh, Y., Yana, I., Ohno, H. & Seiki, M. Cytoplasmic tail-dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity. J Cell Biol 155, 1345–1356 (2001).

Vinogradova, T. et al. Concerted effort of centrosomal and Golgi-derived microtubules is required for proper Golgi complex assembly but not for maintenance. Mol Biol Cell 23, 820–833 (2012).

Nobutani, K. et al. Absence of primary cilia in cell cycle-arrested human breast cancer cells. Genes Cells 19, 141–152 (2014).

Reilova-Velez, J. & Seiler, M. W. Abnormal cilia in a breast carcinoma. An ultrastructural study. Arch Pathol Lab Med 108, 795–797 (1984).

Yuan, K. et al. Primary cilia are decreased in breast cancer: analysis of a collection of human breast cancer cell lines and tissues. J Histochem Cytochem 58, 857–870 (2010).

Wong, S. Y. et al. Primary cilia can both mediate and suppress Hedgehog pathway-dependent tumorigenesis. Nat Med 15, 1055–1061 (2009).

Schraml, P. et al. Sporadic clear cell renal cell carcinoma but not the papillary type is characterized by severely reduced frequency of primary cilia. Mod Pathol 22, 31–36 (2009).

Spektor, A., Tsang, W. Y., Khoo, D. & Dynlacht, B. D. Cep97 and CP110 suppress a cilia assembly program. Cell 130, 678–690 (2007).

Greer, Y. E. et al. Casein kinase 1delta functions at the centrosome and Golgi to promote ciliogenesis. Mol Biol Cell 25, 1629–1640 (2014).

Kani, S. et al. The receptor tyrosine kinase Ror2 associates with and is activated by casein kinase Iepsilon. J Biol Chem 279, 50102–50109 (2004).

Bai, M. et al. ARFGAP1 promotes AP-2-dependent endocytosis. Nat Cell Biol 13, 559–567 (2011).

Watanabe, Y. et al. Fezf1 is required for penetration of the basal lamina by olfactory axons to promote olfactory development. J Comp Neurol 515, 565–584 (2009).

Bolte, S. & Cordelieres, F. P. A guided tour into subcellular colocalization analysis in light microscopy. J Microsc 224, 213–232 (2006).

Chan, K. T., Cortesio, C. L. & Huttenlocher, A. Integrins in cell migration. Methods Enzymol 426, 47–67 (2007).