Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 + 2083 word(s) 2083 2021-07-08 12:06:49 |
2 update references and layout Meta information modification 2083 2021-07-20 03:13:23 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Kim, N. CrkL during Bone Remodeling. Encyclopedia. Available online: https://encyclopedia.pub/entry/12207 (accessed on 29 March 2024).
Kim N. CrkL during Bone Remodeling. Encyclopedia. Available at: https://encyclopedia.pub/entry/12207. Accessed March 29, 2024.
Kim, Nacksung. "CrkL during Bone Remodeling" Encyclopedia, https://encyclopedia.pub/entry/12207 (accessed March 29, 2024).
Kim, N. (2021, July 20). CrkL during Bone Remodeling. In Encyclopedia. https://encyclopedia.pub/entry/12207
Kim, Nacksung. "CrkL during Bone Remodeling." Encyclopedia. Web. 20 July, 2021.
CrkL during Bone Remodeling
Edit

Coupled signaling between bone-forming osteoblasts and bone-resorbing osteoclasts is crucial to the maintenance of bone homeostasis. We previously reported that v-crk avian sarcoma virus CT10 oncogene homolog-like (CrkL), which belongs to the Crk family of adaptors, inhibits bone morphogenetic protein 2 (BMP2)-mediated osteoblast differentiation, while enhancing receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation. In this study, we investigated whether CrkL can also regulate the coupling signals between osteoblasts and osteoclasts, facilitating bone homeostasis. Osteoblastic CrkL strongly decreased RANKL expression through its inhibition of runt-related transcription factor 2 (Runx2) transcription. Reduction in RANKL expression by CrkL in osteoblasts resulted in the inhibition of not only osteoblast-dependent osteoclast differentiation but also osteoclast-dependent osteoblast differentiation, suggesting that CrkL participates in the coupling signals between osteoblasts and osteoclasts via its regulation of RANKL expression. Therefore, CrkL bifunctionally regulates osteoclast differentiation through both a direct and indirect mechanism while it inhibits osteoblast differentiation through its blockade of both BMP2 and RANKL reverse signaling pathways. Collectively, these data suggest that CrkL is involved in bone homeostasis, where it helps to regulate the complex interactions of the osteoblasts, osteoclasts, and their coupling signals.

osteoclast osteoblast RANKL coupling signal CrkL bone homeostasis

​​​​​​​​1. Introduction

Bone is a complex and dynamic tissue, and it undergoes continuous renewal via bone remodeling processes to maintain appropriate bone mass and quality [1]. These continuous processes of synthesis and destruction are fine-tuned by an equilibrium between bone-forming osteoblasts and bone-resorbing osteoclasts [2][3]. In addition to the inherent functions of osteoblasts and osteoclasts, they contribute to each other’s functions via direct and indirect communication to maintain bone homeostasis [4][5][6][7]. Moreover, osteoblasts can influence osteoclastic bone resorption by producing osteoclast regulatory factors, such as macrophage colony-stimulating factor (M-CSF), receptor activator of nuclear factor kappa-B ligand (RANKL), Fas ligand, complement component 3a, and semaphorins [5][8][9][10][11][12][13][14][15][16]. Additionally, various osteoclast-derived factors, such as those released from the matrix, secreted from the osteoclast, and expressed on the cell membrane, can also influence the osteoblast differentiation and function [16][17]. For example, matrix-derived factors, such as transforming growth factor β, BMP2, and insulin-like growth factors, which are released from osteoclastic bone resorption sites on the bone surface, stimulate the differentiation of the osteoblast progenitors. Osteoclasts also secrete products, such as BMP6, sphingosine-1-phosphate, and Wnt-10b to promote osteoblast precursor recruitment and differentiation. In addition, osteoclast membrane-bound factors, such as ephrin B2 and semaphorin D, are expected to support various interactions between the osteoclasts and mature osteoblasts promoting their osteoblastic activity [17]. The communication between osteoclasts and osteoblasts is often the cause of the side effects of the presently available antiresorptive agents and anabolic agents for the treatment of bone disease [18][19][20][21][22]. Therefore, a more detailed understanding of the cellular and molecular mechanisms of bone remodeling is necessary to identify and explore new therapeutic targets for bone disorders.
The cytoplasmic adaptor CrkL (v-crk avian sarcoma virus CT10 oncogene homolog-like) belongs to the Crk family of adaptors and is comprised of a single N-terminal Src homology 2 (SH2) domain and two consecutive SH3 domains (nSH3 and cSH3). CrkL is ubiquitously expressed in most tissues and exhibits several biological functions, such as adhesion, proliferation, migration, and survival [23][24][25][26]. This adaptor protein can function via an interaction between its own SH2 or SH3 domain and numerous adaptor proteins, including paxillin, p130Cas, p120 c-cbl, insulin receptor substrate proteins, STAT5, and PI3K [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. We previously found that CrkII, another adaptor in the Crk family, plays a pivotal role in osteoclast and osteoblast differentiation [41][42]. CrkII enhances osteoclast differentiation by activating Rac1, whereas it inhibits osteoblast differentiation via JNK activation [41][42]. Furthermore, CrkII and CrkL exhibit overlapping functions in certain processes, including osteoclast and osteoblast differentiation, as they share several binding partners, due to remarkable homology between them. In contrast, several studies have reported that Crk proteins exhibit separate functions, notably during development [43][44]. We previously reported that CrkL and CrkII show redundant function during osteoclast and osteoblast differentiation, as CrkL is a distinct gene transcribed from the CrkL locus but not Crk locus. The role of CrkL in communication between osteoclasts and osteoblasts during bone remodeling processes remains unknown; therefore, in the present study, we thoroughly investigated the role of CrkL during bone remodeling by considering various aspects.

2.Bifunctional Role of CrkL during Bone Remodeling

2.1. CrkL Has a Positive and Negative Effect on Osteoclast and Osteoblast Differentiation, Respectively

We previously reported that CrkL and CrkII exhibit overlapping functions in osteoclasts and osteoblasts. In the present study, to confirm the roles of CrkL in osteoclasts and osteoblasts, we determined the effects of retrovirus-mediated overexpression of CrkL in bone marrow-derived monocyte/macrophage lineage cells (BMMs) and primary osteoblasts. The formation of large multinucleated osteoclasts, induced by RANKL, was significantly enhanced in BMMs overexpressing CrkL compared to that in control (Figure 1a); however, alkaline phosphate (ALP) activity and bone mineralization induced by osteogenic media (OGM) was significantly inhibited in osteoblasts overexpressing CrkL (Figure 1b). These results confirmed that CrkL upregulates RANKL-mediated osteoclast differentiation, while it downregulates osteoblast differentiation and function.
Figure 1. CrkL enhances osteoclast differentiation, while it inhibits osteoblast differentiation. (a) TRAP staining images. Osteoclast differentiation of BMMs overexpressing the control or CrkL retrovirus following treatment with M-CSF, or M-CSF and RANKL (left panel). Number of TRAP-positive multinuclear cells (right panel). Bar: 200 µm. (b,c) Primary osteoblast precursors overexpressing the control or CrkL retrovirus were cultured in OGM. (b) ALP activity assay. (c) Alizarin red staining images (left panel). Quantification of alizarin red staining intensities (right panel). # p < 0.05; * p < 0.01 as compared with the controls.

2.2. CrkL Indirectly Inhibits Osteoclast Differentiation by Regulating RANKL (Tnfsf11) Expression

Osteoblasts produce RANKL and osteoprotegerin (OPG), that contribute to bone homeostasis via the regulation of osteoclastogenesis [15]. We further examined whether CrkL is associated with osteoblast-mediated osteoclast differentiation. Overexpression of CrkL in osteoblasts significantly inhibited the mRNA expression of Tnfsf11 in both nonstimulated and 1,25 (OH)2 vitamin D3 (Vit D3)-stimulated osteoblasts without affecting the OPG (Tnfrsf11b) expression (Figure 2a). Conversely, downregulation of CrkL by siRNA led to an increase in the mRNA levels of Tnfsf11 (Figure 2b). To functionally validate the role of CrkL in osteoblastic RANKL expression, we cocultured the osteoblasts with osteoclast precursor cells. The coculture of osteoblasts overexpressing or downregulating CrkL with osteoclast precursor cells displayed decreased or increased osteoclast formation, in contrast to each control osteoblast culture (Figure 2c,d).
Figure 2. CrkL attenuates RANKL expression. (a) Primary osteoblast precursors overexpressing the control or CrkL retrovirus in the presence or absence of Vit D3. mRNA expression of the indicated genes. (b) Primary osteoblast precursors were transfected with control or CrkL siRNAs in the presence or absence of Vit D3. mRNA expression of the indicated genes was assessed by real-time PCR. (c) Primary osteoblast precursors overexpressing the control or CrkL retrovirus were cocultured with BMMs and Vit D3 in the presence or absence of PGE2. TRAP staining images (left panel) where used to enumerate the number of TRAP-positive multinuclear cells (right panel). Bar: 200 µm. (d) Primary osteoblast precursors transfected with control or CrkL siRNAs and cocultured with BMMs and Vit D3 in the presence or absence of PGE2. TRAP staining images (left panel) where used to enumerate the number of TRAP-positive multinuclear cells (right panel). Bar: 200 µm. (e) Osteoclast differentiation in BMMs, cocultured with osteoblasts, treated as indicated in the presence of Vit D3 and PGE2. TRAP staining images (left panel) where used to enumerate the number of TRAP-positive multinuclear cells (right panel) in each sample. Bar: 200 µm. # p < 0.05; * p < 0.01; ** p < 0.001 as compared with the controls.
To further assess the role of CrkL in osteoblast-mediated osteoclast differentiation, osteoblast and osteoclast precursor cells were transduced with control or CrkL retrovirus, as illustrated in Figure 2e, and then cocultured in the presence of vitamin D3 (Vit D3) and prostaglandin E2 (PGE2). Interestingly, a significant decrease in osteoclast formation was observed when BMMs overexpressing CrkL were cocultured with osteoblasts overexpressing CrkL, compared to the control (Figure 2e). These results indicated that CrkL inhibits osteoblast-mediated osteoclast differentiation by blocking RANKL expression, though it increases RANKL-mediated osteoclast differentiation in osteoclast precursor cells.

2.3. CrkL Inhibits RANKL-Mediated Osteoblast Differentiation

Recently, it has been reported that vesicular receptor activator of nuclear factor kappa-B (RANK) secreted from mature osteoclasts activates RANKL reverse signaling in osteoblasts and enhances osteoblast differentiation [45]. Moreover, the W9 peptide, which is known to bind RANKL and inhibits RANKL-induced osteoclast differentiation in vitro, also binds RANKL on osteoblasts and promotes osteoblast differentiation, presumably via RANKL reverse signaling [46][47][48]. Therefore, we tested the effects of CrkL on W9-induced osteoblast differentiation, to evaluate whether the inhibition of RANKL expression in osteoblasts caused by CrkL affects osteoblast differentiation by regulating RANKL reverse signaling. As illustrated in Figure 3, overexpression of CrkL in osteoblasts significantly inhibited W9-induced bone mineralization. Consistent with bone mineralization, expression of typical osteogenic marker genes, including Runx2, alkaline phosphatase (Alpl), and bone sialoprotein (Ibsp), was significantly inhibited by CrkL overexpression (Figure 3a,b). In contrast, downregulation of endogenous CrkL expression markedly increased the ALP activity, bone mineralization, and expression of typical osteogenic marker genes (Figure 3c–e). Collectively, these results indicate that osteoblastic CrkL regulates osteoblast differentiation by inhibiting both BMP2 signaling and RANKL reverse signaling.
Figure 3. CrkL inhibits RANKL–RANK reverse signaling pathway. (a,b) Primary osteoblast precursors overexpressing the control or CrkL retrovirus were cultured in OGM supplemented with W9. (a) Alizarin red staining images (left panel) allowed for the quantification of the alizarin red staining intensities (right panel) under each condition. (b) mRNA expression of the indicated genes. (ce) Primary osteoblast precursors transfected with control or CrkL siRNAs were cultured in OGM with W9. (c) ALP activity assay. (d) Alizarin red staining images (left panel). Quantification of alizarin red staining intensities (right panel). (e) mRNA expression of the indicated genes. # p < 0.05; * p < 0.01; ** p < 0.001 as compared with the controls.

2.4. CrkL Inhibits RANKL Expression via Interaction with Runx2

As Runx2 has been implicated in RANKL expression in various cell types, such as prostate cancer cells, vascular smooth muscle cells, and osteoblasts [49][50][51][52], we further examined whether CrkL-inhibited Tnfsf11 expression is involved in the regulation of Runx2 expression. As illustrated in Figure 4a, Runx2 expression controlled by CrkL was similar to that of Tnfsf11. Moreover, the expression of Tnfsf11 as well as that of Runx2 was suppressed when CrkL was overexpressed, whereas it was increased when CrkL was downregulated. Moreover, inhibition of Tnfsf11 expression by CrkL was rescued by the forced expression of Runx2 (Figure 4b). In order to gain a deeper insight into the mechanisms underlying the inhibition of Tnfsf11 expression by CrkL, we examined whether CrkL directly interacts with Runx2. Coimmunoprecipitation revealed the direct interaction between CrkL and Runx2 in HEK-293T cells (Figure 4c). Furthermore, Runx2 induced the expression of 6XOSE (Runx2 DNA-binding elements), Ibsp, and Tnfsf11 promoter reporter, and its effects were significantly inhibited by CrkL (Figure 4d). Collectively, these results indicated that the CrkL-induced decreased expression of RANKL is mediated via the suppression of Runx2 transcriptional activity.
Figure 4. CrkL inhibits Runx2 transcriptional activity. (a) Primary osteoblast precursors overexpressing control or CrkL retrovirus and primary osteoblast precursors transfected with control or CrkL-siRNAs were cultured in the presence or absence of Vit D3. (b) Primary osteoblast precursors overexpressing control, CrkL or CrkL and Runx2 were cultured in the presence or absence of Vit D3. mRNA expression of Tnfsf11. (c) Co-immunoprecipitation assays in Runx2 or Runx2 and CrkL-transfected HEK-293T cells. (d) Luciferase assay of HEK-293T cells transfected with various expression plasmids. # p < 0.05; * p < 0.01; ** p < 0.001 as compared with the controls.

2.5. Downregulation of CrkL Can Protect RANKL-Induced Bone Loss In Vivo

Eventually, we assessed the local administration of siRNA, targeting CrkL, in a mouse calvaria model. In microcomputed tomography (µCT) analyses, the injection of RANKL to the calvaria led to a significant decrease in bone mass. RANKL-induced bone loss was attenuated by the local administration of CrkL siRNA (Figure 5). These results indicated that CrkL may be a potential target in the development of new therapeutics for bone diseases.
Figure 5. CrkL knockdown prevents RANKL-induced bone loss. Bone volume to tissue volume (BV/TV) and the number of TRAP-positive cells in the murine calvarial model treated with PBS, RANKL and control, or CrkL siRNA. # p < 0.05; * p < 0.01 as compared with the controls.

3. Conclusions

CrkL inhibits BMP2-mediated osteoblast differentiation of the osteoblast precursors, while enhancing RANKL-induced osteoclast differentiation of the osteoclast precursors. CrkL also affects both osteoblast-dependent osteoclast differentiation and osteoclast-dependent osteoblast differentiation via its suppression of RANKL expression in osteoblasts. Further evaluations of the in vivo roles of CrkL during bone remodeling will help to understand the potential therapeutic value of CrkL in the future treatment of various bone diseases.

References

  1. Walsh, M.C.; Kim, N.; Kadono, Y.; Rho, J.; Lee, S.Y.; Lorenzo, J.; Choi, Y. Osteoimmunology: Interplay between the immune system and bone metabolism. Annu. Rev. Immunol. 2006, 24, 33–63.
  2. Cappariello, A.; Maurizi, A.; Veeriah, V.; Teti, A. The Great Beauty of the osteoclast. Arch. Biochem. Biophys. 2014, 558, 70–78.
  3. Kim, J.H.; Kim, N. Signaling Pathways in Osteoclast Differentiation. Chonnam Med. J. 2016, 52, 12–17.
  4. Kim, B.J.; Koh, J.M. Coupling factors involved in preserving bone balance. Cell. Mol. Life Sci. 2019, 76, 1243–1253.
  5. Rodan, G.A.; Martin, T.J. Role of osteoblasts in hormonal control of bone resorption—A hypothesis. Calcif. Tissue Int. 1981, 33, 349–351.
  6. Tamma, R.; Zallone, A. Osteoblast and osteoclast crosstalks: From OAF to Ephrin. Inflamm. Allergy Drug Targets 2012, 11, 196–200.
  7. Mundy, G.R.; Eleftesriou, F. Boning up on ephrin signaling. Cell 2006, 126, 441–443.
  8. Sambandam, Y.; Blanchard, J.J.; Daughtridge, G.; Kolb, R.J.; Shanmugarajan, S.; Pandruvada, S.N.; Bateman, T.A.; Reddy, S.V. Microarray profile of gene expression during osteoclast differentiation in modelled microgravity. J. Cell. Biochem. 2010, 111, 1179–1187.
  9. Anderson, D.M.; Maraskovsky, E.; Billingsley, W.L.; Dougall, W.C.; Tometsko, M.E.; Roux, E.R.; Teepe, M.C.; DuBose, R.F.; Cosman, D.; Galibert, L. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997, 390, 175–179.
  10. Wong, B.R.; Rho, J.; Arron, J.; Robinson, E.; Orlinick, J.; Chao, M.; Kalachikov, S.; Cayani, E.; Bartlett, F.S., 3rd; Frankel, W.N.; et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J. Biol. Chem. 1997, 272, 25190–25194.
  11. Wang, L.; Liu, S.; Zhao, Y.; Liu, D.; Liu, Y.; Chen, C.; Karray, S.; Shi, S.; Jin, Y. Osteoblast-induced osteoclast apoptosis by fas ligand/FAS pathway is required for maintenance of bone mass. Cell Death Differ. 2015, 22, 1654–1664.
  12. Matsuoka, K.; Park, K.A.; Ito, M.; Ikeda, K.; Takeshita, S. Osteoclast-derived complement component 3a stimulates osteoblast differentiation. J. Bone Miner. Res. 2014, 29, 1522–1530.
  13. Negishi-Koga, T.; Shinohara, M.; Komatsu, N.; Bito, H.; Kodama, T.; Friedel, R.H.; Takayanagi, H. Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat. Med. 2011, 17, 1473–1480.
  14. Zhang, Y.; Wei, L.; Miron, R.J.; Shi, B.; Bian, Z. Anabolic bone formation via a site-specific bone-targeting delivery system by interfering with semaphorin 4D expression. J. Bone Miner. Res. 2015, 30, 286–296.
  15. Chen, X.; Wang, Z.; Duan, N.; Zhu, G.; Schwarz, E.M.; Xie, C. Osteoblast-osteoclast interactions. Connect. Tissue Res. 2018, 59, 99–107.
  16. Yuan, F.L.; Wu, Q.Y.; Miao, Z.N.; Xu, M.H.; Xu, R.S.; Jiang, D.L.; Ye, J.X.; Chen, F.H.; Zhao, M.D.; Wang, H.J.; et al. Osteoclast-Derived Extracellular Vesicles: Novel Regulators of Osteoclastogenesis and Osteoclast-Osteoblasts Communication in Bone Remodeling. Front. Physiol. 2018, 9, 628.
  17. Sims, N.A.; Martin, T.J. Coupling Signals between the Osteoclast and Osteoblast: How are Messages Transmitted between These Temporary Visitors to the Bone Surface? Front. Endocrinol. 2015, 6, 41.
  18. Chang, B.; Quan, Q.; Li, Y.; Qiu, H.; Peng, J.; Gu, Y. Treatment of Osteoporosis, with a Focus on 2 Monoclonal Antibodies. Med Sci. Monit. 2018, 24, 8758–8766.
  19. Qaseem, A.; Forciea, M.A.; McLean, R.M.; Denberg, T.D. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. Ann. Intern. Med. 2017, 166, 818–839.
  20. Cotts, K.G.; Cifu, A.S. Treatment of Osteoporosis. JAMA 2018, 319, 1040–1041.
  21. Rachner, T.D.; Khosla, S.; Hofbauer, L.C. Osteoporosis: Now and the future. Lancet 2011, 377, 1276–1287.
  22. Cosman, F.; de Beur, S.J.; LeBoff, M.S.; Lewiecki, E.M.; Tanner, B.; Randall, S.; Lindsay, R. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014, 25, 2359–2381.
  23. Shigeno-Nakazawa, Y.; Kasai, T.; Ki, S.; Kostyanovskaya, E.; Pawlak, J.; Yamagishi, J.; Okimoto, N.; Taiji, M.; Okada, M.; Westbrook, J.; et al. A pre-metazoan origin of the CRK gene family and co-opted signaling network. Sci. Rep. 2016, 6, 34349.
  24. Roy, N.H.; Mammadli, M.; Burkhardt, J.K.; Karimi, M. CrkL is required for donor T cell migration to GvHD target organs. Oncotarget 2020, 11, 1505–1514.
  25. Song, Q.; Yi, F.; Zhang, Y.; Li, D.K.J.; Wei, Y.; Yu, H.; Zhang, Y. CRKL regulates alternative splicing of cancer-related genes in cervical cancer samples and HeLa cell. BMC Cancer 2019, 19, 499.
  26. Birge, R.B.; Kalodimos, C.; Inagaki, F.; Tanaka, S. Crk and CrkL adaptor proteins: Networks for physiological and pathological signaling. Cell Commun. Signal. 2009, 7, 13.
  27. Ren, R.; Ye, Z.S.; Baltimore, D. Abl protein-tyrosine kinase selects the Crk adapter as a substrate using SH3-binding sites. Genes Dev. 1994, 8, 783–795.
  28. Sakai, R.; Iwamatsu, A.; Hirano, N.; Ogawa, S.; Tanaka, T.; Mano, H.; Yazaki, Y.; Hirai, H. A novel signaling molecule, p130, forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner. EMBO J. 1994, 13, 3748–3756.
  29. De Jong, R.; ten Hoeve, J.; Heisterkamp, N.; Groffen, J. Crkl is complexed with tyrosine-phosphorylated Cbl in Ph-positive leukemia. J. Biol. Chem. 1995, 270, 21468–21471.
  30. Salgia, R.; Uemura, N.; Okuda, K.; Li, J.L.; Pisick, E.; Sattler, M.; de Jong, R.; Druker, B.; Heisterkamp, N.; Chen, L.B.; et al. CRKL links p210BCR/ABL with paxillin in chronic myelogenous leukemia cells. J. Biol. Chem. 1995, 270, 29145–29150.
  31. Salgia, R.; Pisick, E.; Sattler, M.; Li, J.L.; Uemura, N.; Wong, W.K.; Burky, S.A.; Hirai, H.; Chen, L.B.; Griffin, J.D. p130CAS forms a signaling complex with the adapter protein CRKL in hematopoietic cells transformed by the BCR/ABL oncogene. J. Biol. Chem. 1996, 271, 25198–25203.
  32. Ribon, V.; Hubbell, S.; Herrera, R.; Saltiel, A.R. The product of the cbl oncogene forms stable complexes in vivo with endogenous Crk in a tyrosine phosphorylation-dependent manner. Mol. Cell. Biol. 1996, 16, 45–52.
  33. Beitner-Johnson, D.; Blakesley, V.A.; Shen-Orr, Z.; Jimenez, M.; Stannard, B.; Wang, L.M.; Pierce, J.; LeRoith, D. The proto-oncogene product c-Crk associates with insulin receptor substrate-1 and 4PS. Modulation by insulin growth factor-I (IGF) and enhanced IGF-I signaling. J. Biol. Chem. 1996, 271, 9287–9290.
  34. Sattler, M.; Salgia, R.; Okuda, K.; Uemura, N.; Durstin, M.A.; Pisick, E.; Xu, G.; Li, J.L.; Prasad, K.V.; Griffin, J.D. The proto-oncogene product p120CBL and the adaptor proteins CRKL and c-CRK link c-ABL, p190BCR/ABL and p210BCR/ABL to the phosphatidylinositol-3’ kinase pathway. Oncogene 1996, 12, 839–846.
  35. Akagi, T.; Shishido, T.; Murata, K.; Hanafusa, H. v-Crk activates the phosphoinositide 3-kinase/AKT pathway in transformation. Proc. Natl. Acad. Sci. USA 2000, 97, 7290–7295.
  36. Sattler, M.; Salgia, R.; Shrikhande, G.; Verma, S.; Uemura, N.; Law, S.F.; Golemis, E.A.; Griffin, J.D. Differential signaling after beta1 integrin ligation is mediated through binding of CRKL to p120(CBL) and p110(HEF1). J. Biol. Chem. 1997, 272, 14320–14326.
  37. Sattler, M.; Salgia, R.; Shrikhande, G.; Verma, S.; Pisick, E.; Prasad, K.V.; Griffin, J.D. Steel factor induces tyrosine phosphorylation of CRKL and binding of CRKL to a complex containing c-kit, phosphatidylinositol 3-kinase, and p120(CBL). J. Biol. Chem. 1997, 272, 10248–10253.
  38. Gesbert, F.; Garbay, C.; Bertoglio, J. Interleukin-2 stimulation induces tyrosine phosphorylation of p120-Cbl and CrkL and formation of multimolecular signaling complexes in T lymphocytes and natural killer cells. J. Biol. Chem. 1998, 273, 3986–3993.
  39. Koval, A.P.; Karas, M.; Zick, Y.; LeRoith, D. Interplay of the proto-oncogene proteins CrkL and CrkII in insulin-like growth factor-I receptor-mediated signal transduction. J. Biol. Chem. 1998, 273, 14780–14787.
  40. Fish, E.N.; Uddin, S.; Korkmaz, M.; Majchrzak, B.; Druker, B.J.; Platanias, L.C. Activation of a CrkL-stat5 signaling complex by type I interferons. J. Biol. Chem. 1999, 274, 571–573.
  41. Kim, J.H.; Kim, K.; Kim, I.; Seong, S.; Nam, K.I.; Kim, K.K.; Kim, N. Adaptor protein CrkII negatively regulates osteoblast differentiation and function through JNK phosphorylation. Exp. Mol. Med. 2019, 51, 1–10.
  42. Kim, J.H.; Kim, K.; Kim, I.; Seong, S.; Nam, K.I.; Lee, S.H.; Kim, K.K.; Kim, N. Role of CrkII Signaling in RANKL-Induced Osteoclast Differentiation and Function. J. Immunol. 2016, 196, 1123–1131.
  43. Guris, D.L.; Fantes, J.; Tara, D.; Druker, B.J.; Imamoto, A. Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome. Nat. Genet. 2001, 27, 293–298.
  44. Park, T.J.; Boyd, K.; Curran, T. Cardiovascular and craniofacial defects in Crk-null mice. Mol. Cell Biol. 2006, 26, 6272–6282.
  45. Ikebuchi, Y.; Aoki, S.; Honma, M.; Hayashi, M.; Sugamori, Y.; Khan, M.; Kariya, Y.; Kato, G.; Tabata, Y.; Penninger, J.M.; et al. Coupling of bone resorption and formation by RANKL reverse signalling. Nature 2018, 561, 195–200.
  46. Ozaki, Y.; Koide, M.; Furuya, Y.; Ninomiya, T.; Yasuda, H.; Nakamura, M.; Kobayashi, Y.; Takahashi, N.; Yoshinari, N.; Udagawa, N. Treatment of OPG-deficient mice with WP9QY, a RANKL-binding peptide, recovers alveolar bone loss by suppressing osteoclastogenesis and enhancing osteoblastogenesis. PLoS ONE 2017, 12, e0184904.
  47. Sawa, M.; Wakitani, S.; Kamei, N.; Kotaka, S.; Adachi, N.; Ochi, M. Local administration of WP9QY (W9) peptide promotes bone formation in a rat femur delayed-union model. J. Bone Miner. Metab. 2018, 36, 383–391.
  48. Otsuki, Y.; Ii, M.; Moriwaki, K.; Okada, M.; Ueda, K.; Asahi, M. W9 peptide enhanced osteogenic differentiation of human adipose-derived stem cells. Biochem. Biophys. Res. Commun. 2018, 495, 904–910.
  49. Geoffroy, V.; Kneissel, M.; Fournier, B.; Boyde, A.; Matthias, P. High bone resorption in adult aging transgenic mice overexpressing cbfa1/runx2 in cells of the osteoblastic lineage. Mol. Cell. Biol. 2002, 22, 6222–6233.
  50. Enomoto, H.; Shiojiri, S.; Hoshi, K.; Furuichi, T.; Fukuyama, R.; Yoshida, C.A.; Kanatani, N.; Nakamura, R.; Mizuno, A.; Zanma, A.; et al. Induction of osteoclast differentiation by Runx2 through receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin regulation and partial rescue of osteoclastogenesis in Runx2−/− mice by RANKL transgene. J. Biol. Chem. 2003, 278, 23971–23977.
  51. Yahiro, Y.; Maeda, S.; Morikawa, M.; Koinuma, D.; Jokoji, G.; Ijuin, T.; Komiya, S.; Kageyama, R.; Miyazono, K.; Taniguchi, N. BMP-induced Atoh8 attenuates osteoclastogenesis by suppressing Runx2 transcriptional activity and reducing the Rankl/Opg expression ratio in osteoblasts. Bone Res. 2020, 8, 32.
  52. Byon, C.H.; Sun, Y.; Chen, J.; Yuan, K.; Mao, X.; Heath, J.M.; Anderson, P.G.; Tintut, Y.; Demer, L.L.; Wang, D.; et al. Runx2-upregulated receptor activator of nuclear factor κB ligand in calcifying smooth muscle cells promotes migration and osteoclastic differentiation of macrophages. Arterioscler. Thromb. Vasc. Biol. 2011, 31, 1387–1396.
More
Information
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
View Times: 476
Revisions: 2 times (View History)
Update Date: 20 Jul 2021
1000/1000