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A matricellular protein and EGF-like repeat signalling in the social amoebozoan Dictyostelium discoideum

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Abstract

Matricellular proteins interact with the extracellular matrix (ECM) and modulate cellular processes by binding to cell surface receptors and initiating intracellular signal transduction. Their association with the ECM and the ability of some members of this protein family to regulate cell motility have opened up new avenues of research to investigate their functions in normal and diseased cells. In this review, we summarize the research on CyrA, an ECM calmodulin-binding protein in Dictyostelium. CyrA is proteolytically cleaved into smaller EGF-like (EGFL) repeat containing cleavage products during development. The first EGFL repeat of CyrA binds to the cell surface and activates a novel signalling pathway that modulates cell motility in this model organism. The similarity of CyrA to the most well-characterized matricellular proteins in mammals allows it to be designated as the first matricellular protein identified in Dictyostelium.

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Abbreviations

AcbA:

Acyl-CoA binding protein A

ADAMTS:

A disintegrin and mettaloproteinase with thrombospondin motifs

carA:

cAMP receptor A

carC:

cAMP receptor C

CaM:

Calmodulin

CaMBP:

CaM-binding protein

CyrA:

Cysteine-rich protein A

CyrA-C40:

40 kDa CyrA cleavage product

CyrA-C45:

45 kDa CyrA cleavage product

ECM:

Extracellular matrix

EGFL:

Epidermal growth factor-like

EGFL1:

CyrA EGFL repeat 1

EGFR:

EGF receptor

ER:

Endoplasmic reticulum

MHC:

Myosin II heavy chain

MMP2:

Matrix metalloproteinase 2

PaxB:

Paxillin B

PI3K:

Phosphatidylinositol-3-kinase

PKA:

Protein kinase A

PLA2:

Phospholipase A2

PLC:

Phospholipase C

SDF-2:

Spore differentiation factor 2

SPARC:

Secreted protein acidic and rich in cysteine

TalB:

Talin B

Ten14:

14th EGFL repeat of tenascin C

Tenascin C:

Tenascin cytotactin

TSP:

Thrombospondin

VinB:

Vinculin B

References

  1. Bornstein P, Sage EH (2002) Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol 14:608–616

    Article  PubMed  CAS  Google Scholar 

  2. Mosher DF, Adams JC (2012) Adhesion-modulating/matricellular ECM protein families: a structural, functional and evolutionary appraisal. Matrix Biol 31:155–161

    Article  PubMed  CAS  Google Scholar 

  3. Roberts DD (2011) Emerging functions of matricellular proteins. Cell Mol Life Sci 68:3133–3136

    Article  PubMed  CAS  Google Scholar 

  4. Adams JC, Lawler J (2011) The thrombospondins. Cold Spring Harb Perspect Biol 3:a009712

    Article  PubMed  Google Scholar 

  5. Bradshaw AD (2012) Diverse biological functions of the SPARC family of proteins. Int J Biochem Cell Biol 44:480–488

    Article  PubMed  CAS  Google Scholar 

  6. Özbek S, Balasubramanian PG, Chiquet-Ehrismann R, Tucker RP, Adams JC (2010) The evolution of extracellular matrix. Mol Biol Cell 21:4300–4305

    Article  PubMed  Google Scholar 

  7. Murphy-Ullrich JE (2001) The de-adhesive activity of matricellular proteins: is intermediate cell adhesion an adaptive state? J Clin Invest 107:785–790

    Article  PubMed  CAS  Google Scholar 

  8. Brekken RA, Sage EH (2000) SPARC, a matricellular protein: at the crossroads of cell-matrix communication. Matrix Biol 19:569–580

    Article  PubMed  CAS  Google Scholar 

  9. Yanagisawa H, Schluterman MK, Brekken RA (2009) Fibulin-5, an integrin-binding matricellular protein: its function in development and disease. J Cell Commun Signal 3:337–347

    Article  PubMed  Google Scholar 

  10. Weaver MS, Workman G, Cardo-Vila M, Arap W, Pasqualini R, Sage EH (2010) Processing of the matricellular protein hevin in mouse brain is dependent on ADAMTS4. J Biol Chem 285:5868–5877

    Article  PubMed  CAS  Google Scholar 

  11. Apte SS (2009) A disintegrin-like and metalloproteinase (reprolysin-type) with thrombospondin type I motif (ADAMTS) superfamily-functions and mechanisms. J Biol Chem 284:31493–31497

    Article  PubMed  CAS  Google Scholar 

  12. Appella E, Weber I, Blasi F (1988) Structure and function of epidermal growth factor-like regions in proteins. FEBS Lett 231:1–4

    Article  PubMed  CAS  Google Scholar 

  13. Grotendorst GR, Soma Y, Takehara K, Charette M (1989) EGF and TGF-alpha are potent chemoattractants for endothelial cells and EGF-like peptides are present at sites of tissue regeneration. J Cell Physiol 139:617–623

    Article  PubMed  CAS  Google Scholar 

  14. Linggi B, Carpenter G (2006) ErbB receptors: new insights on mechanisms and biology. Trends Cell Biol 16:649–656

    Article  PubMed  CAS  Google Scholar 

  15. Rao Z, Handford P, Mayhew M, Knott V, Browniee GC, Stuart D (1995) The structure of a Ca2+-binding epidermal growth factor-like domain: its role in protein–protein interactions. Cell 82:131–141

    Article  PubMed  CAS  Google Scholar 

  16. Campbell I, Bork P (1993) Epidermal growth factor-like modules. Curr Opin Struct Biol 3:385–392

    Article  CAS  Google Scholar 

  17. Kurucz E, Márkus R, Zsámboki J, Folkl-Medzihradszky K, Darula Z, Vilmos P, Udvardy A, Krausz I, Lukacsovich T, Gateff E, Zettervall CJ, Hultmark D, Andó I (2007) Nimrod, a putative phagocytosis receptor with EGF repeats in Drosophila plasmatocytes. Curr Biol 17:649–654

    Article  PubMed  CAS  Google Scholar 

  18. Glöckner G, Eichinger L, Szafranski K, Pachebat JA, Bankier AT, Dear PH, Lehmann R, Baumgart C, Parra G, Abril JF, Guigó R, Kumpf K, Tunggal B, Cox E, Quail MA, Platzer M, Rosenthal A, Noegel AA (2002) Sequence and analysis of chromosome 2 of Dictyostelium discoideum. Nature 418:79–85

    Article  PubMed  Google Scholar 

  19. Fey P, Stephens S, Titus MA, Chisholm RL (2002) SadA, a novel adhesion receptor in Dictyostelium. J Cell Biol 159:1109–1119

    Article  PubMed  CAS  Google Scholar 

  20. Huber RJ, O’Day DH (2009) An EGF-like peptide sequence from Dictyostelium enhances cell motility and chemotaxis. Biochem Biophys Res Commun 379:470–475

    Article  PubMed  CAS  Google Scholar 

  21. Suarez A, Huber RJ, Myre MA, O’Day DH (2011) An extracellular matrix, calmodulin-binding protein from Dictyostelium with EGF-like repeats that enhance cell motility. Cell Signal 23:1197–1206

    Article  PubMed  CAS  Google Scholar 

  22. Jones FS, Jones PL (2000) The tenascin family of ECM glycoproteins: structure, function, and regulation during embryonic development and tissue remodelling. Dev Dyn 218:235–259

    Article  PubMed  CAS  Google Scholar 

  23. Wallner K, Li C, Shah PK, Wu KJ, Schwartz SM, Sharifi BG (2004) EGF-Like domain of tenascin-C is proapoptotic for cultured smooth muscle cells. Arterioscler Thromb Vasc Biol 24:1416–1421

    Article  PubMed  CAS  Google Scholar 

  24. Chen P, Gupta K, Wells A (1994) Cell movement elicited by epidermal growth factor receptor requires kinase and autophosphorylation but is separable from mitogenesis. J Cell Biol 124:547–555

    Article  PubMed  CAS  Google Scholar 

  25. Tsunoda T, Inada H, Kalembeyi I, Imanaka-Yoshida K, Sakakibara M, Okada R, Katsuta K, Sakakura T, Majima Y, Yoshida T (2003) Involvement of large tenascin-C splice variants in breast cancer progression. Am J Pathol 162:1857–1867

    Article  PubMed  CAS  Google Scholar 

  26. Iyer AK, Kien TT, Borysenko CW, Cascio M, Camacho CJ, Blair HC, Bahar I, Wells A (2007) Tenascin cytotactin epidermal growth factor-like repeat binds epidermal growth factor receptor with low affinity. J Cell Physiol 211:748–758

    Article  PubMed  CAS  Google Scholar 

  27. Iyer AKV, Tran KT, Griffith L, Wells A (2008) Cell surface restriction of EGFR by a tenascin cytotactin-encoded EGF-like repeat is preferential for motility-related signalling. J Cell Physiol 214:504–512

    Article  PubMed  CAS  Google Scholar 

  28. Swindle CS, Tran KT, Johnson TD, Banerjee P, Mayes AM, Griffith L, Wells A (2001) Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor. J Cell Biol 154:459–468

    Article  PubMed  CAS  Google Scholar 

  29. Liu A, Garg P, Yang S, Gong P, Pallero MA, Annis DS, Liu Y, Passaniti A, Mann D, Mosher DF, Murphy-Ullrich JE, Goldblum SE (2009) Epidermal growth factor-like repeats of thrombospondins activate phospholipase Cgamma and increase epithelial cell migration through indirect epidermal growth factor receptor activation. J Biol Chem 284:6389–6402

    Article  PubMed  CAS  Google Scholar 

  30. Fitchev PP, Wcislak SM, Lee C, Bergh A, Brendler CB, Stellmach VM, Crawford SE, Mavroudis CD, Cornwell ML, Doll JA (2010) Thrombospondin-1 regulates the normal prostate in vivo through angiogenesis and TGF-β activation. Lab Invest 90:1078–1090

    Article  PubMed  CAS  Google Scholar 

  31. Schenk S, HIntermann E, Bilban M, Koshikawa N, Hojilla C, Khokha R, Quaranta V (2003) Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMPdependent mammary gland involution. J Cell Biol 161:197–209

    Article  PubMed  CAS  Google Scholar 

  32. Giannelli G, Falk-Marzillier J, Schiraldi O, Stetler-Stevenson WG, Quaranta V (1997) Induction of cell migration by matrix metalloprotease-2 cleavage of laminin 5. Science 277:225–228

    Article  PubMed  CAS  Google Scholar 

  33. Yamamoto H, Itoh F, Iku S, Hosokawa M, Imai K (2001) Expression of the gamma (2) chain of laminin-5 at the invasive front is associated with recurrence and poor prognosis in human esophageal squamous cell carcinoma. Clin Cancer Res 7:896–900

    PubMed  CAS  Google Scholar 

  34. Niki T, Kohno T, Iba S, Moriya Y, Takahashi Y, Saito M, Maeshima A, Yamada T, Matsumo Y, Fukayama M, Yokota J, Hirohashi S (2002) Frequent co-localization of cox-2 and laminin-5 gamma2 chain at the invasive front of early-stage lung adenocarcinomas. Am J Pathol 160:1129–1141

    Article  PubMed  CAS  Google Scholar 

  35. Williams JG (2010) Dictyostelium finds new roles to model. Genetics 185:717–726

    Article  PubMed  CAS  Google Scholar 

  36. Schaap P (2011) Evolutionary crossroads in developmental biology: Dictyostelium discoideum. Development 138:387–396

    Article  PubMed  CAS  Google Scholar 

  37. Jin T, Hereld D (2006) Moving toward understanding eukaryotic chemotaxis. Eur J Cell Biol 85:905–913

    Article  PubMed  CAS  Google Scholar 

  38. Insall R, Andrew N (2007) Chemotaxis in Dictyostelium: how to walk straight using parallel pathways. Curr Opin Microbiol 10:578–581

    Article  PubMed  CAS  Google Scholar 

  39. Chen LF, Iijima M, Tang M, Landree MA, Huang YE, Xiong Y, Iglesias PA, Devreotes PN (2007) PLA2 and PI3K/PTEN pathways act in parallel to mediate chemotaxis. Dev Cell 12:603–614

    Article  PubMed  CAS  Google Scholar 

  40. Van Haastert PJM, Keizer-Gunnink I, Kortholt A (2007) Essential role of PI3-kinase and phospholipase A2 in Dictyostelium discoideum chemotaxis. J Cell Biol 177:809–816

    Article  PubMed  Google Scholar 

  41. Chen L, Janetopoulos C, Huang YE, Iijima M, Borleis J, Devreotes PN (2003) Two phases of actin polymerization display different dependencies on PI (3, 4, 5) P3 accumulation and have unique roles during chemotaxis. Mol Biol Cell 14:5028–5037

    Article  PubMed  CAS  Google Scholar 

  42. Takeda K, Sasaki AT, Ha H, Seung H-A, Firtel RA (2007) Role of phosphatidylinositol 3-kinases in chemotaxis in Dictyostelium. J Biol Chem 282:11874–11884

    Article  PubMed  CAS  Google Scholar 

  43. Veltman DM, Keizer-Gunnik I, Van Haastert PJM (2008) Four key signaling pathways mediating chemotaxis in Dictyostelium discoideum. J Cell Biol 180:747–753

    Article  PubMed  CAS  Google Scholar 

  44. Lusche DF, Wessels D, Soll DR (2009) The effects of extracellular calcium on motility, pseudopod and uropod formation, chemotaxis, and the cortical localization of myosin II in Dictyostelium discoideum. Cell Motil Cytoskeleton 66:567–587

    Article  PubMed  CAS  Google Scholar 

  45. Gauthier ML, O’Day DH (2001) Detection of calmodulin-binding proteins and calmodulin-dependent phosphorylation linked to calmodulin-dependent chemotaxis to folic and cAMP in Dictyostelium. Cell Signal 13:575–584

    Article  PubMed  CAS  Google Scholar 

  46. Scherer A, Kuhl S, Wessels D, Lusche DF, Raisley B, Soll DR (2010) Ca2+ chemotaxis in Dictyostelium discoideum. J Cell Sci 123:3756–3767

    Article  PubMed  CAS  Google Scholar 

  47. Browning DD, The T, O`Day DH (1995) Comparative analysis of chemotaxis in Dictyostelium using a radial bioassay method: protein tyrosine kinase activity is required for chemotaxis to folate but not to cAMP. Cell Signal 7:481–489

    Article  PubMed  CAS  Google Scholar 

  48. Wilkins MR, Williams KL (1995) The extracellular matrix of the Dictyostelium discoideum slug. Experientia 51:1189–1196

    Article  PubMed  CAS  Google Scholar 

  49. Morrison A, Blanton RL, Grimson M, Fuchs M, Williams KL, Williams J (1994) Disruption of the gene encoding the EcmA, extracellular matrix protein of Dictyostelium, alters slug morphology. Dev Biol 163:457–466

    Article  PubMed  CAS  Google Scholar 

  50. Breen EJ, Vardy PH, Williams KL (1987) Movement of the multicellular slug stage of Dictyostelium discoideum: an analytical approach. Development 101:313–321

    Google Scholar 

  51. Grant WN, Williams KL (1983) Monoclonal antibody characterization of the slime sheath: the extracellular matrix of Dictyostelium discoideum. EMBO J 2:935–940

    PubMed  CAS  Google Scholar 

  52. Breen EJ, Williams KL (1988) Movement of the Dictyostelium discoideum slug: models, musings and images. Dev Genet 9:539–548

    Article  PubMed  CAS  Google Scholar 

  53. Kowal AS, Chisholm RL (2011) Uncovering a role for the tail of the Dictyostelium discoideum SadA protein in cell-substrate adhesion. Eukaryot Cell 10:662–671

    Article  PubMed  CAS  Google Scholar 

  54. Huber RJ, Suarez A, O’Day DH (2012) CyrA, a matricellular protein that modulates cell motility in Dictyostelium discoideum. Matrix Biol 31:271–280

    Article  PubMed  CAS  Google Scholar 

  55. Müller-Taubenberger A, Lupas AN, Li H, Ecke M, Simmeth E, Gerisch G (2001) Calreticulin and calnexin in the endoplasmic reticulum are important for phagocytosis. EMBO J 20:6772–6782

    Article  PubMed  Google Scholar 

  56. Anjard C, Loomis WF (2005) Peptide signaling during terminal differentiation of Dictyostelium. Proc Natl Acad Sci USA 102:7607–7611

    Article  PubMed  CAS  Google Scholar 

  57. Bakthavatsalam D, Gomer RH (2010) The secreted proteome profile of developing Dictyostelium discoideum cells. Proteomics 10:2556–2559

    Article  PubMed  CAS  Google Scholar 

  58. Handford PA, Mayhew M, Baron M, Winship PR, Campbell ID, Brownlee GG (1991) Key residues involved in calcium-binding motifs EGF-like domains. Nature 351:164–167

    Article  PubMed  CAS  Google Scholar 

  59. Periz J, Gill AC, Knott V, Handford PA, Tomley FM (2005) Calcium binding activity of the epidermal growth factor-like domains of the apicomplexan microneme protein EtMIC4. Mol Biochem Parasitol 143:192–199

    Article  PubMed  CAS  Google Scholar 

  60. Huber RJ, O’Day DH (2011) EGF-like peptide-enhanced cell motility in Dictyostelium functions independently of the cAMP-mediated pathway and requires active Ca2+/calmodulin signaling. Cell Signal 23:731–738

    Article  PubMed  CAS  Google Scholar 

  61. Nikolaeva I, Huber RJ, O’Day DH (2012) EGF-like peptide of Dictyostelium discoideum is not a chemoattractant but it does restore folate-mediated chemotaxis in the presence of signal transduction inhibitors. Peptides 34:145–149

    Article  PubMed  CAS  Google Scholar 

  62. Huber RJ, O’Day DH (2012) EGF-like peptide-enhanced cell movement in Dictyostelium is mediated by protein kinases and the activity of several cytoskeletal proteins. Cell Signal 24:1770–1780

    Article  PubMed  CAS  Google Scholar 

  63. Bryant JA, Finn RS, Slamon DJ, Cloughesy TF, Charles AC (2004) EGF activates intracellular and intercellular calcium signaling by distinct pathways in tumor cells. Cancer Biol Ther 3:1243–1249

    Article  PubMed  CAS  Google Scholar 

  64. Kato K, Ueoka Y, Tamura T, Nishida J, Wake N (1998) Oncogenic Ras modulates epidermal growth factor responsiveness in endometrial carcinomas. Eur J Cancer 34:737–744

    Article  PubMed  CAS  Google Scholar 

  65. Bolourani P, Spiegelman GB, Weeks G (2006) Delineation of the roles played by RasG and RasC in cAMP-dependent signal transduction during the early development of Dictyostelium discoideum. Mol Biol Cell 17:4543–4550

    Article  PubMed  CAS  Google Scholar 

  66. Zhang H, Heid PJ, Wessels D, Daniels KJ, Pham T, Loomis WF, Soll DR (2003) Constitutively active protein kinase A disrupts motility and chemotaxis in Dictyostelium discoideum. Eukaryot Cell 2:62–75

    Article  PubMed  CAS  Google Scholar 

  67. Zandi R, Larsen AB, Andersen P, Stockhausen MT, Poulsen HS (2007) Mechanisms for oncogenic activation of the epidermal growth factor receptor. Cell Signal 19:2013–2023

    Article  PubMed  CAS  Google Scholar 

  68. Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310

    Article  PubMed  CAS  Google Scholar 

  69. Wu L, Valkema R, Van Haastert PJ, Devreotes PN (1995) The G protein beta subunit is essential for multiple responses to chemoattractants in Dictyostelium. J Cell Biol 129:1667–1675

    Article  PubMed  CAS  Google Scholar 

  70. Sasaki AT, Janetopoulos C, Lee S, Charest PG, Takeda K, Sundheimer LW, Meili R, Devreotes PN, Firtel RA (2007) G protein-independent Ras/PI3K/F-actin circuit regulates basic cell motility. J Cell Biol 178:185–191

    Article  PubMed  CAS  Google Scholar 

  71. Varnum A, Soll DR (1981) Chemoresponsiveness to cAMP and folic acid during growth, development, and dedifferentiation in Dictyostelium discoideum. Differentiation 18:151–160

    Article  PubMed  CAS  Google Scholar 

  72. Gallant ND, Michael KE, García AJ (2005) Cell adhesion strengthening: contributions of adhesive area, integrin binding, and focal adhesion assembly. Mol Biol Cell 16:4329–4340

    Article  PubMed  CAS  Google Scholar 

  73. Ziegler WH, Liddington RC, Critchley DR (2006) The structure and regulation of vinculin. Trends Cell Biol 16:453–460

    Article  PubMed  CAS  Google Scholar 

  74. Diasio RB, Fourie J (2006) Targeting the epidermal growth factor receptor in the treatment of colorectal cancer. Drugs 66:1441–1463

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This review was supported by a Discovery Grant (D.H.O’D.; A6807) and a Canada Graduate Scholarship (R.J.H.) from the Natural Sciences and Engineering Research Council of Canada.

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Correspondence to Robert J. Huber.

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Huber, R.J., O’Day, D.H. A matricellular protein and EGF-like repeat signalling in the social amoebozoan Dictyostelium discoideum . Cell. Mol. Life Sci. 69, 3989–3997 (2012). https://doi.org/10.1007/s00018-012-1068-4

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