Skip to main content
SpringerLink
Log in

Ihog proteins contribute to integrin-mediated focal adhesions

  • Research Paper
  • Published:
Science China Life Sciences Aims and scope Submit manuscript

Abstract

Integrin expression forms focal adhesions, but how this process is physiologically regulated is unclear. Ihog proteins are evolutionarily conserved, playing roles in Hedgehog signaling and serving as trans-homophilic adhesion molecules to mediate cell-cell interactions. Whether these proteins are also engaged in other cell adhesion processes remains unknown. Here, we report that Drosophila Ihog proteins function in the integrin-mediated adhesions. Removal of Ihog proteins causes blister and spheroidal muscle in wings and embryos, respectively. We demonstrate that Ihog proteins interact with integrin via the extracellular portion and that their removal perturbs integrin distribution. Finally, we show that Boc, a mammalian Ihog protein, rescues the embryonic defects caused by removing its Drosophila homologs. We thus propose that Ihog proteins contribute to integrin-mediated focal adhesions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Allen, B.L., Song, J.Y., Izzi, L., Althaus, I.W., Kang, J.S., Charron, F., Krauss, R.S., and McMahon, A.P. (2011). Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function. Dev Cell 20, 775–787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anderson, C., Thorsteinsdottir, S., and Borycki, A.G. (2009). Sonic hedgehog-dependent synthesis of laminin α1 controls basement membrane assembly in the myotome. Development 136, 3495–3504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baade, T., Paone, C., Baldrich, A., and Hauck, C.R. (2019). Clustering of integrin β cytoplasmic domains triggers nascent adhesion formation and reveals a protozoan origin of the integrin-talin interaction. Sci Rep 9, 5728.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bergeron, S.A., Tyurina, O.V., Miller, E., Bagas, A., and Karlstrom, R.O. (2011). Brother of cdo (umleitung) is cell-autonomously required for Hedgehog-mediated ventral CNS patterning in the zebrafish. Development 138, 75–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bökel, C., and Brown, N.H. (2002). Integrins in development. Dev Cell 3, 311–321.

    Article  PubMed  Google Scholar 

  • Bouvard, D., Brakebusch, C., Gustafsson, E., Aszodi, A., Bengtsson, T., Berna, A., and Fassler, R. (2001). Functional consequences of integrin gene mutations in mice. Circ Res 89, 211–223.

    Article  CAS  PubMed  Google Scholar 

  • Briscoe, J., and Thérond, P.P. (2013). The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 14, 416–429.

    Article  PubMed  Google Scholar 

  • Brower, D.L., Bunch, T.A., Mukai, L., Adamson, T.E., Wehrli, M., Lam, S., Friedlander, E., Roote, C.E., and Zusman, S. (1995). Nonequivalent requirements for PS1 and PS2 integrin at cell attachments in Drosophila: genetic analysis of the alpha PS1 integrin subunit. Development 121, 1311–1320.

    Article  CAS  PubMed  Google Scholar 

  • Brower, D.L., Wilcox, M., Piovant, M., Smith, R.J., and Reger, L.A. (1984). Related cell-surface antigens expressed with positional specificity in Drosophila imaginal discs. Proc Natl Acad Sci USA 81, 7485–7489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brown, N.H. (2000). An integrin chicken and egg problem: which comes first, the extracellular matrix or the cytoskeleton? Curr Opin Cell Biol 12, 629–633.

    Article  CAS  PubMed  Google Scholar 

  • Brown, N.H., Gregory, S.L., and Martin-Bermudo, M.D. (2000). Integrins as mediators of morphogenesis in Drosophila. Dev Biol 223, 1–16.

    Article  CAS  PubMed  Google Scholar 

  • Brown, N.H., Gregory, S.L., Rickoll, W.L., Fessler, L.I., Prout, M., White, R.A.H., and Fristrom, J.W. (2002). Talin is essential for integrin function in Drosophila. Dev Cell 3, 569–579.

    Article  CAS  PubMed  Google Scholar 

  • Bulgakova, N.A., Klapholz, B., and Brown, N.H. (2012). Cell adhesion in Drosophila: versatility of cadherin and integrin complexes during development. Curr Opin Cell Biol 24, 702–712.

    Article  CAS  PubMed  Google Scholar 

  • Calderwood, D.A. (2004). Integrin activation. J Cell Sci 117, 657–666.

    Article  CAS  PubMed  Google Scholar 

  • Calderwood, D.A., Shattil, S.J., and Ginsberg, M.H. (2000). Integrins and actin filaments: reciprocal regulation of cell adhesion and signaling. J Biol Chem 275, 22607–22610.

    Article  CAS  PubMed  Google Scholar 

  • Camp, D., Currie, K., Labbé, A., van Meyel, D.J., and Charron, F. (2010). Ihog and Boi are essential for Hedgehog signaling in Drosophila. Neural Dev 5, 28.

    Article  PubMed  PubMed Central  Google Scholar 

  • Capdevila, J., and Guerrero, I. (1994). Targeted expression of the signaling molecule decapentaplegic induces pattern duplications and growth alterations in Drosophila wings. EMBO J 13, 4459–4468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chi-Rosso, G., Gotwals, P.J., Yang, J., Ling, L., Jiang, K., Chao, B., Baker, D.P., Burkly, L.C., Fawell, S.E., and Koteliansky, V.E. (1997). Fibronectin type III repeats mediate RGD-independent adhesion and signaling through activated β1 integrins. J Biol Chem 272, 31447–31452.

    Article  CAS  PubMed  Google Scholar 

  • Clark, K.A., McGrail, M., and Beckerle, M.C. (2003). Analysis of PINCH function in Drosophila demonstrates its requirement in integrin-dependent cellular processes. Development 130, 2611–2621.

    Article  CAS  PubMed  Google Scholar 

  • Classen, A.K., Aigouy, B., Giangrande, A., and Eaton, S. (2008). Imaging Drosophila pupal wing morphogenesis. In: Dahmann, C., eds. Drosophila. Methods in Molecular Biology, vol 420. Clifton: Humana Press. 265–275.

    Google Scholar 

  • Devenport, D., and Brown, N.H. (2004). Morphogenesis in the absence of integrins: mutation of both Drosophila β subunits prevents midgut migration. Development 131, 5405–5415.

    Article  CAS  PubMed  Google Scholar 

  • Evans, E.A., and Calderwood, D.A. (2007). Forces and bond dynamics in cell adhesion. Science 316, 1148–1153.

    Article  CAS  PubMed  Google Scholar 

  • Evans, R., Patzak, I., Svensson, L., De Filippo, K., Jones, K., McDowall, A., and Hogg, N. (2009). Integrins in immunity. J Cell Sci 122, 215–225.

    Article  CAS  PubMed  Google Scholar 

  • Fournier-Thibault, C., Blavet, C., Jarov, A., Bajanca, F., Thorsteinsdóttir, S., and Duband, J.L. (2009). Sonic hedgehog regulates integrin activity, cadherin contacts, and cell polarity to orchestrate neural tube morphogenesis. J Neurosci 29, 12506–12520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ganguly, K.K., Pal, S., Moulik, S., and Chatterjee, A. (2013). Integrins and metastasis. Cell Adhes Migration 7, 251–261.

    Article  Google Scholar 

  • Goel, H.L., Underwood, J.M., Nickerson, J.A., Hsieh, C.C., and Languino, L.R. (2010). β1 integrins mediate cell proliferation in three-dimensional cultures by regulating expression of the sonic hedgehog effector protein, GLI1. J Cell Physiol 224, 210–217.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Horwitz, A.F. (1997). Integrins and health. Sci Am 276, 68–75.

    Article  CAS  PubMed  Google Scholar 

  • Hsia, E.Y.C., Zhang, Y., Tran, H.S., Lim, A., Chou, Y.H., Lan, G., Beachy, P.A., and Zheng, X. (2017). Hedgehog mediated degradation of Ihog adhesion proteins modulates cell segregation in Drosophila wing imaginal discs. Nat Commun 8, 1275.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hynes, R.O. (2002). Integrins: bidirectional, allosteric signaling machines. Cell 110, 673–687.

    Article  CAS  PubMed  Google Scholar 

  • Iwamoto, D.V., and Calderwood, D.A. (2015). Regulation of integrin-mediated adhesions. Curr Opin Cell Biol 36, 41–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Izzi, L., Lévesque, M., Morin, S., Laniel, D., Wilkes, B.C., Mille, F., Krauss, R.S., McMahon, A.P., Allen, B.L., and Charron, F. (2011). Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation. Dev Cell 20, 788–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jia, J., Tong, C., Wang, B., Luo, L., and Jiang, J. (2004). Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature 432, 1045–1050.

    Article  CAS  PubMed  Google Scholar 

  • Johnson, M.S., Lu, N., Denessiouk, K., Heino, J., and Gullberg, D. (2009). Integrins during evolution: evolutionary trees and model organisms. Biochim Biophys Acta (BBA)-Biomembranes 1788, 779–789.

    Article  CAS  PubMed  Google Scholar 

  • Jones, R.G., Li, X., Gray, P.D., Kuang, J., Clayton, F., Samowitz, W.S., Madison, B.B., Gumucio, D.L., and Kuwada, S.K. (2006). Conditional deletion of β1 integrins in the intestinal epithelium causes a loss of Hedgehog expression, intestinal hyperplasia, and early postnatal lethality. J Cell Biol 175, 505–514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kadrmas, J.L., Smith, M.A., Clark, K.A., Pronovost, S.M., Muster, N., Yates III, J.R., and Beckerle, M.C. (2004). The integrin effector PINCH regulates JNK activity and epithelial migration in concert with Ras suppressor 1. J Cell Biol 167, 1019–1024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang, J.S., Mulieri, P.J., Hu, Y., Taliana, L., and Krauss, R.S. (2002). BOC, an Ig superfamily member, associates with CDO to positively regulate myogenic differentiation. EMBO J 21, 114–124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang, J.S., Mulieri, P.J., Miller, C., Sassoon, D.A., and Krauss, R.S. (1998). CDO, a robo-related cell surface protein that mediates myogenic differentiation. J Cell Biol 143, 403–413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, C., Ye, F., and Ginsberg, M.H. (2011). Regulation of integrin activation. Annu Rev Cell Dev Biol 27, 321–345.

    Article  CAS  PubMed  Google Scholar 

  • Klapholz, B., and Brown, N.H. (2017). Talin — the master of integrin adhesions. J Cell Sci 130, 2435–2446.

    CAS  PubMed  Google Scholar 

  • Leptin, M., Bogaert, T., Lehmann, R., and Wilcox, M. (1989). The function of PS integrins during Drosophila embryogenesis. Cell 56, 401–408.

    Article  CAS  PubMed  Google Scholar 

  • Li, B., Chi, X., Song, J., Tang, Y., Du, J., He, X., Sun, X., Bi, Z., Wang, Y., Zhan, J., et al. (2019). Integrin-interacting protein Kindlin-2 induces mammary tumors in transgenic mice. Sci China Life Sci 62, 225–234.

    Article  CAS  PubMed  Google Scholar 

  • Li, R., Mitra, N., Gratkowski, H., Vilaire, G., Litvinov, R., Nagasami, C., Weisel, J.W., Lear, J.D., DeGrado, W.F., and Bennett, J.S. (2003). Activation of integrin αIIbß3 by modulation of transmembrane helix associations. Science 300, 795–798.

    Article  CAS  PubMed  Google Scholar 

  • Lum, L., Yao, S., Mozer, B., Rovescalli, A., Von Kessler, D., Nirenberg, M., and Beachy, P.A. (2003). Identification of hedgehog pathway components by RNAi in Drosophila cultured cells. Science 299, 2039–2045.

    Article  CAS  PubMed  Google Scholar 

  • Maartens, A.P., and Brown, N.H. (2015). The many faces of cell adhesion during Drosophila muscle development. Dev Biol 401, 62–74.

    Article  CAS  PubMed  Google Scholar 

  • Martin-Bermudo, M.D., and Brown, N.H. (1996). Intracellular signals direct integrin localization to sites of function in embryonic muscles. J Cell Biol 134, 217–226.

    Article  CAS  PubMed  Google Scholar 

  • McLellan, J.S., Yao, S., Zheng, X., Geisbrecht, B.V., Ghirlando, R., Beachy, P.A., and Leahy, D.J. (2006). Structure of a heparin-dependent complex of Hedgehog and Ihog. Proc Natl Acad Sci USA 103, 17208–17213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miranti, C.K., and Brugge, J.S. (2002). Sensing the environment: a historical perspective on integrin signal transduction. Nat Cell Biol 4, E83–E90.

    Article  CAS  PubMed  Google Scholar 

  • Okada, A., Charron, F., Morin, S., Shin, D.S., Wong, K., Fabre, P.J., Tessier-Lavigne, M., and McConnell, S.K. (2006). Boc is a receptor for sonic hedgehog in the guidance of commissural axons. Nature 444, 369–373.

    Article  CAS  PubMed  Google Scholar 

  • Paulus, W., Baur, I., Schuppan, D., and Roggendorf, W. (1993). Characterization of integrin receptors in normal and neoplastic human brain. Am J Pathol 143, 154–163.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pribila, J.T., Quale, A.C., Mueller, K.L., and Shimizu, Y. (2004). Integrins and T cell-mediated immunity. Annu Rev Immunol 22, 157–180.

    Article  CAS  PubMed  Google Scholar 

  • Prokop, A., Martin-Bermudo, M.D., Bate, M., and Brown, N.H. (1998). Absence of PS integrins or laminin A affects extracellular adhesion, but not intracellular assembly, of hemiadherens and neuromuscular junctions in Drosophila embryos. Dev Biol 196, 58–76.

    Article  CAS  PubMed  Google Scholar 

  • Ramachandran, P., and Budnik, V. (2010). Preparation of early Drosophila embryonic fillets (before cuticle deposition). Cold Spring Harb Protoc 2010(10), pdb.prot5497.

  • Ross, R.S., and Borg, T.K. (2001). Integrins and the myocardium. Circ Res 88, 1112–1119.

    Article  CAS  PubMed  Google Scholar 

  • Rothwell, W.F., and Sullivan, W. (2007). Drosophila embryo dechorionation. Cold Spring Harb Protoc 2007, pdb.prot4826.

    Article  Google Scholar 

  • Ruoslahti, E., and Pierschbacher, M.D. (1987). New perspectives in cell adhesion: RGD and integrins. Science 238, 491–497.

    Article  CAS  PubMed  Google Scholar 

  • Swedlow, J. (2011). Immunolabeling of Drosophila embryos and tissues. Cold Spring Harb Protoc 2011, pdb.prot5657.

    Article  Google Scholar 

  • Tadokoro, S., Shattil, S.J., Eto, K., Tai, V., Liddington, R.C., de Pereda, J.M., Ginsberg, M.H., and Calderwood, D.A. (2003). Talin binding to integrin ß tails: a final common step in integrin activation. Science 302, 103–106.

    Article  CAS  PubMed  Google Scholar 

  • Tanentzapf, G., and Brown, N.H. (2006). An interaction between integrin and the talin FERM domain mediates integrin activation but not linkage to the cytoskeleton. Nat Cell Biol 8, 601–606.

    Article  CAS  PubMed  Google Scholar 

  • Tanentzapf, G., Devenport, D., Godt, D., and Brown, N.H. (2007). Integrin-dependent anchoring of a stem-cell niche. Nat Cell Biol 9, 1413–1418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tenzen, T., Allen, B.L., Cole, F., Kang, J.S., Krauss, R.S., and McMahon, A.P. (2006). The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev Cell 10, 647–656.

    Article  CAS  PubMed  Google Scholar 

  • Torgler, C.N., Narasimha, M., Knox, A.L., Zervas, C.G., Vernon, M.C., and Brown, N.H. (2004). Tensin stabilizes integrin adhesive contacts in Drosophila. Dev Cell 6, 357–369.

    Article  CAS  PubMed  Google Scholar 

  • Watt, F.M. (2002). Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J 21, 3919–3926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weinstein, A. (1918). Coincidence of crossing over in Drosophila melanogaster (Ampelophila). Genetics 3, 135–172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wright, T.R.F. (1960). The phenogenetics of the embryonic mutant lethal myospheroid, in Drosophila melanogaster. J Exp Zool 143, 77–99.

    Article  CAS  PubMed  Google Scholar 

  • Wu, X., Zhang, Y., Chuang, K.H., Cai, X., Ajaz, H., and Zheng, X. (2019). The Drosophila Hedgehog receptor component Interference hedgehog (Ihog) mediates cell-cell interactions through trans-homophilic binding. J Biol Chem 294, 12339–12348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yan, D., Wu, Y., Yang, Y., Belenkaya, T.Y., Tang, X., and Lin, X. (2010). The cell-surface proteins Dally-like and Ihog differentially regulate Hedgehog signaling strength and range during development. Development 137, 2033–2044.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yao, S., Lum, L., and Beachy, P. (2006). The ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell 125, 343–357.

    Article  CAS  PubMed  Google Scholar 

  • Zervas, C.G., Gregory, S.L., and Brown, N.H. (2001). Drosophila integrin-linked kinase is required at sites of integrin adhesion to link the cytoskeleton to the plasma membrane. J Cell Biol 152, 1007–1018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng, X., Mann, R.K., Sever, N., and Beachy, P.A. (2010). Genetic and biochemical definition of the Hedgehog receptor. Genes Dev 24, 57–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by National Natural Science Foundation of China (91754109, 31771544, 31730044). We thank D.J. Van Meyel and F. Charron, the TRiP at Harvard Medical School, National Institute of Genetics and Mitsubishi Kagaku Institute of Life Sciences, Tsinghua Fly Center and Bloomington Drosophila Stock Center for fly stocks; P. Beachy and Hybridoma Bank for antibodies. We thank Dr. Hong Xu and Chiara Dart at NIH/NHLBI for language editing

Author information

Author notes

  1. Han Liu

    Present address: Human Phenome Institute, Fudan University, Shanghai, 200433, China

Authors and Affiliations

  1. The State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200433, China

    Yun Qi, Han Liu, Kang Zhang, Chenghao Shen & Xinhua Lin

  2. The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100864, China

    Yihui Wu

Authors
  1. Yun Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Han Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yihui Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chenghao Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xinhua Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yun Qi or Xinhua Lin.

Ethics declarations

Compliance and ethics The authors declare no competing financial interests

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qi, Y., Liu, H., Zhang, K. et al. Ihog proteins contribute to integrin-mediated focal adhesions. Sci. China Life Sci. 66, 366–375 (2023). https://doi.org/10.1007/s11427-022-2154-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-022-2154-1

Keywords

Search

Navigation