Browse > Article
http://dx.doi.org/10.14348/molcells.2019.0189

ST5 Positively Regulates Osteoclastogenesis via Src/Syk/Calcium Signaling Pathways  

Kim, Min Kyung (Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute (DRI), School of Dentistry, Seoul National University)
Kim, Bongjun (Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute (DRI), School of Dentistry, Seoul National University)
Kwon, Jun-Oh (Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute (DRI), School of Dentistry, Seoul National University)
Song, Min-Kyoung (Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute (DRI), School of Dentistry, Seoul National University)
Jung, Suhan (Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute (DRI), School of Dentistry, Seoul National University)
Lee, Zang Hee (Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute (DRI), School of Dentistry, Seoul National University)
Kim, Hong-Hee (Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute (DRI), School of Dentistry, Seoul National University)
Publication Information
Molecules and Cells / v.42, no.11, 2019 , pp. 810-819 More about this Journal
Abstract
For physiological or pathological understanding of bone disease caused by abnormal behavior of osteoclasts (OCs), functional studies of molecules that regulate the generation and action of OCs are required. In a microarray approach, we found the suppression of tumorigenicity 5 (ST5) gene is upregulated by receptor activator of nuclear $factor-{\kappa}B$ ligand (RANKL), the OC differentiation factor. Although the roles of ST5 in cancer and ${\beta}-cells$ have been reported, the function of ST5 in bone cells has not yet been investigated. Knockdown of ST5 by siRNA reduced OC differentiation from primary precursors. Moreover, ST5 downregulation decreased expression of NFATc1, a key transcription factor for osteoclastogenesis. In contrast, overexpression of ST5 resulted in the opposite phenotype of ST5 knockdown. In immunocytochemistry experiments, the ST5 protein is colocalized with Src in RANKL-committed cells. In addition, ST5 enhanced activation of Src and Syk, a Src substrate, in response to RANKL. ST5 reduction caused a decrease in RANKL-evoked calcium oscillation and inhibited translocation of NFATc1 into the nucleus. Taken together, these findings provide the first evidence of ST5 involvement in positive regulation of osteoclastogenesis via Src/Syk/calcium signaling.
Keywords
calcium; NFATc1; osteoclasts; RANKL; Src; suppression of tumorigenicity 5; Syk;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 Darnay, B.G., Ni, J., Moore, P.A., and Aggarwal, B.B. (1999). Activation of NF-kappaB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif. J. Biol. Chem. 274, 7724-7731.   DOI
2 Destaing, O., Sanjay, A., Itzstein, C., Horne, W.C., Toomre, D., De Camilli, P., and Baron, R. (2008). The tyrosine kinase activity of c-Src regulates actin dynamics and organization of podosomes in osteoclasts. Mol. Biol. Cell 19, 394-404.   DOI
3 Evans, K.E. and Fox, S.W. (2007). Interleukin-10 inhibits osteoclastogenesis by reducing NFATc1 expression and preventing its translocation to the nucleus. BMC Cell Biol. 8, 4.   DOI
4 Hayman, A.R. (2008). Tartrate-resistant acid phosphatase (TRAP) and the osteoclast/immune cell dichotomy. Autoimmunity 41, 218-223.   DOI
5 Ioannou, M.S., Bell, E.S., Girard, M., Chaineau, M., Hamlin, J.N.R., Daubaras, M., Monast, A., Park, M., Hodgson, L., and McPherson, P.S. (2015). DENND2B activates Rab13 at the leading edge of migrating cells and promotes metastatic behavior. J. Cell Biol. 208, 629-648.   DOI
6 Kim, J.H. and Kim, N. (2014). Regulation of NFATc1 in Osteoclast Differentiation. J. Bone Metab. 21, 233-241.   DOI
7 Kim, K., Kim, J.H., Lee, J., Jin, H.M., Kook, H., Kim, K.K., Lee, S.Y., and Kim, N. (2007). MafB negatively regulates RANKL-mediated osteoclast differentiation. Blood 109, 3253-3259.   DOI
8 Kim, K., Kim, J.H., Moon, J.B., Lee, J., Kwak, H.B., Park, Y.W., and Kim, N. (2012). The transmembrane adaptor protein, linker for activation of T cells (LAT), regulates RANKL-induced osteoclast differentiation. Mol. Cells 33, 401-406.   DOI
9 Kim, N., Takami, M., Rho, J., Josien, R., and Choi, Y. (2002). A novel member of the leukocyte receptor complex regulates osteoclast differentiation. J. Exp. Med. 195, 201-209.   DOI
10 Koga, T., Inui, M., Inoue, K., Kim, S., Suematsu, A., Kobayashi, E., Iwata, T., Ohnishi, H., Matozaki, T., Kodama, T., et al. (2004). Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428, 758-763.   DOI
11 Kurochkina, N. and Guha, U. (2013). SH3 domains: modules of proteinprotein interactions. Biophys. Rev. 5, 29-39.   DOI
12 Lee, Y.D., Yoon, S.H., Ji, E., and Kim, H.H. (2015a). Caveolin-1 regulates osteoclast differentiation by suppressing cFms degradation. Exp. Mol. Med. 47, e192.   DOI
13 Lee, Y.D., Yoon, S.H., Park, C.K., Lee, J., Lee, Z.H., and Kim, H.H. (2015b). Caveolin-1 regulates osteoclastogenesis and bone metabolism in a sexdependent manner. J. Biol. Chem. 290, 6522-6530.   DOI
14 Levy-Apter, E., Finkelshtein, E., Vemulapalli, V., Li, S.S., Bedford, M.T., and Elson, A. (2014). Adaptor protein GRB2 promotes Src tyrosine kinase activation and podosomal organization by protein-tyrosine phosphatase in osteoclasts. J. Biol. Chem. 289, 36048-36058.   DOI
15 Li, B., Boast, S., de los Santos, K., Schieren, I., Quiroz, M., Teitelbaum, S.L., Tondravi, M.M., and Goff, S.P. (2000). Mice deficient in Abl are osteoporotic and have defects in osteoblast maturation. Nat. Genet. 24, 304-308.   DOI
16 Lichy, J.H., Modi, W.S., Seuanez, H.N., and Howley, P.M. (1992). Identification of a human chromosome 11 gene which is differentially regulated in tumorigenic and nontumorigenic somatic cell hybrids of HeLa cells. Cell Growth Differ. 3, 541-548.
17 Oh, H., Ozkirimli, E., Shah, K., Harrison, M.L., and Geahlen, R.L. (2007). Generation of an analog-sensitive Syk tyrosine kinase for the study of signaling dynamics from the B cell antigen receptor. J. Biol. Chem. 282, 33760-33768.   DOI
18 Majidi, M., Gutkind, J.S., and Lichy, J.H. (2000). Deletion of the COOH terminus converts the ST5 p70 protein from an inhibitor of RAS signaling to an activator with transforming activity in NIH-3T3 cells. J. Biol. Chem. 275, 6560-6565.   DOI
19 Majidi, M., Hubbs, A.E., and Lichy, J.H. (1998). Activation of extracellular signal-regulated kinase 2 by a novel Abl-binding protein, ST5. J. Biol. Chem. 273, 16608-16614.   DOI
20 Miyamoto, H., Katsuyama, E., Miyauchi, Y., Hoshi, H., Miyamoto, K., Sato, Y., Kobayashi, T., Iwasaki, R., Yoshida, S., Mori, T., et al. (2012). An essential role for STAT6-STAT1 protein signaling in promoting macrophage cell-cell fusion. J. Biol. Chem. 287, 32479-32484.   DOI
21 Ou, K., Zhang, J., Jiao, Y., Wang, Z.V., Scherer, P., and Kaestner, K.H. (2018). Overexpression of ST5, an activator of Ras, has no effect on beta-cell proliferation in adult mice. Mol. Metab. 11, 212-217.   DOI
22 Park, J.H., Lee, N.K., and Lee, S.Y. (2017). Current understanding of RANK signaling in osteoclast differentiation and maturation. Mol. Cells 40, 706-713.   DOI
23 Ren, R., Mayer, B.J., Cicchetti, P., and Baltimore, D. (1993). Identification of a ten-amino acid proline-rich SH3 binding site. Science 259, 1157-1161.   DOI
24 Rho, J., Takami, M., and Choi, Y. (2004). Osteoimmunology: interactions of the immune and skeletal systems. Mol. Cells 17, 1-9.
25 Ryu, J., Kim, H.J., Chang, E.J., Huang, H., Banno, Y., and Kim, H.H. (2006). Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling. EMBO J. 25, 5840-5851.   DOI
26 Takayanagi, H., Ogasawara, K., Hida, S., Chiba, T., Murata, S., Sato, K., Takaoka, A., Yokochi, T., Oda, H., Tanaka, K., et al. (2000). T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-${\gamma}$. Nature 408, 600-605.   DOI
27 Schwartzberg, P.L., Xing, L., Hoffmann, O., Lowell, C.A., Garrett, L., Boyce, B.F., and Varmus, H.E. (1997). Rescue of osteoclast function by transgenic expression of kinase-deficient Src in src-/- mutant mice. Genes Dev. 11, 2835-2844.   DOI
28 Takayanagi, H. (2005). Mechanistic insight into osteoclast differentiation in osteoimmunology. J. Mol. Med. 83, 170-179.   DOI
29 Takayanagi, H., Kim, S., Koga, T., Nishina, H., Isshiki, M., Yoshida, H., Saiura, A., Isobe, M., Yokochi, T., Inoue, J., et al. (2002). Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell 3, 889-901.   DOI
30 Tomomura, M., Hasegawa, H., Suda, N., Sakagami, H., and Tomomura, A. (2012). Serum calcium-decreasing factor, caldecrin, inhibits receptor activator of NF-${\kappa}B$ ligand (RANKL)-mediated Ca2+ signaling and actin ring formation in mature osteoclasts via suppression of Src signaling pathway. J. Biol. Chem. 287, 17963-17974.   DOI
31 Barrow, A.D., Raynal, N., Andersen, T.L., Slatter, D.A., Bihan, D., Pugh, N., Cella, M., Kim, T., Rho, J., Negishi-Koga, T., et al. (2011). OSCAR is a collagen receptor that costimulates osteoclastogenesis in DAP12-deficient humans and mice. J. Clin. Invest. 121, 3505-3516.   DOI
32 Varin, A., Pontikoglou, C., Labat, E., Deschaseaux, F., and Sensebe, L. (2013). CD200R/CD200 inhibits osteoclastogenesis: new mechanism of osteoclast control by mesenchymal stem cells in human. PLoS One 8, e72831.   DOI
33 Wintges, K., Beil, F.T., Albers, J., Jeschke, A., Schweizer, M., Claass, B., Tiegs, G., Amling, M., and Schinke, T. (2013). Impaired bone formation and increased osteoclastogenesis in mice lacking chemokine (C-C motif) ligand 5 (Ccl5). J. Bone Miner. Res. 28, 2070-2080.   DOI
34 Alexandropoulos, K. and Baltimore, D. (1996). Coordinate activation of c-Src by SH3- and SH2-binding sites on a novel p130Cas-related protein, Sin. Genes Dev. 10, 1341-1355.   DOI
35 Arias-Salgado, E.G., Lizano, S., Sarkar, S., Brugge, J.S., Ginsberg, M.H., and Shattil, S.J. (2003). Src kinase activation by direct interaction with the integrin ${\beta}$ cytoplasmic domain. Proc. Natl. Acad. Sci. U. S. A. 100, 13298-13302.   DOI
36 Asagiri, M., Sato, K., Usami, T., Ochi, S., Nishina, H., Yoshida, H., Morita, I., Wagner, E.F., Mak, T.W., Serfling, E., et al. (2005). Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J. Exp. Med. 202, 1261-1269.   DOI
37 Zaidi, M. (2007). Skeletal remodeling in health and disease. Nat. Med. 13, 791.   DOI
38 Yadav, S.S. and Miller, W.T. (2007). Cooperative activation of Src family kinases by SH3 and SH2 ligands. Cancer Lett. 257, 116-123.   DOI
39 Yamasaki, T., Ariyoshi, W., Okinaga, T., Adachi, Y., Hosokawa, R., Mochizuki, S., Sakurai, K., and Nishihara, T. (2014). The dectin 1 agonist curdlan regulates osteoclastogenesis by inhibiting nuclear factor of activated T cells cytoplasmic 1 (NFATc1) through Syk kinase. J. Biol. Chem. 289, 19191-19203.   DOI
40 Yoon, S.H., Lee, Y., Kim, H.J., Lee, Z.H., Hyung, S.W., Lee, S.W., and Kim, H.H. (2009). Lyn inhibits osteoclast differentiation by interfering with PLCgamma1-mediated Ca2+ signaling. FEBS Lett. 583, 1164-1170.   DOI
41 Boyle, W.J., Simonet, W.S., and Lacey, D.L. (2003). Osteoclast differentiation and activation. Nature 423, 337-342.   DOI