Cell adhesion - ECM remodeling

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ECM remodeling

Extracellular matrix (ECM) remodeling is involved in normal physiological processes, such as embryonic development, reproduction, proliferation, cell motility and adhesion, wound healing, angiogenesis, as well as in disease processes, such as arthritis and metastasis. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade various components of the ECM in these processes. MMPs are divided into six groups, depending on their structure and substrate specificity: 1) Collagenases, such as MMP-1 and MMP-13, 2) Gelatinases, such as Gelatinase-A (MMP-2) and Gelatinase-B (MMP-9), 3) Stromelysins, such as Stromelysin-1 (MMP-3) and Stromelysin-2 (MMP-10), 4) Matrilysins, such as Matrilysin (MMP-7), 5) Membrane-type MMPs (MT-MMPs), such as the type-I transmembrane proteins MMP-14, MMP-15, and MMP-16,. 6) Other MMPs, such as MMP-12 [1].

Endogenous tissue inhibitors of metalloproteinases (TIMPs), such as TIMP1, TIMP2 and TIMP3, reduce excessive proteolytic ECM degradation by MMPs. The balance between activated MMPs and TIMPs controls the extent of ECM remodeling [2], [3].

MMPs are excreted by various connective tissues and pro-inflammatory cells including fibroblasts, osteoblasts, endothelial cells, macrophages, neutrophils, and lymphocytes [4]. These enzymes are expressed as zymogens and are subsequently processed by other MMPs or other classes of proteolytic enzymes [1].

Stromelysin-1 activates a number of proMMPs, including the processing of MMP-1, MMP-13 and Matrilysin (MMP-7) into fully active proteinases [1]. Stromelysin-1 also degrades ECM proteins, e.g., Secreted protein acidic cysteine-rich (Osteonectin), as well as the components of basement membranes, such as Laminin 1 [5], [6], [7].

Stromelysin-2 is involved in the degradation of ECM proteins involved in wound repair, such as Collagen I, Collagen III, and Nidogen. Furthermore, it can activate other MMPs, such as MMP-1 [8].

MMP-2 is not activated by general proteinases, but by membrane MMPs, such as MMP-14, MMP-15, and MMP-16 on the cell surface [9].

Kallikrein serine protease 1 (Kallikrein 1) activates latent MMP-9 involved in the degradation of ECM proteins, such as Collagen I, Collagen II, Collagen III, Collagen IV, and Versican [10], [11], [12], [13].

Plasminogen activator urokinase (PLAU) plays a pivotal role in the regulation of cell adhesion and migration during tissue remodeling. It activates intracellular signaling upon binding to certain receptors on the cell surface. Kallikrein-related peptidase 2 (Kallikrein 2) can cleave PLAU to initiate its proteolytic cascade [14]. PLAU and Plasminogen activator tissue (PLAT) are important components of the extracellular protease system that specifically converts zymogen Plasminogen into Plasmin, the major fibrinolytic protease that is characterized by wide substrate specificity [15]. Plasmin directly degrades ECM proteins, such as Fibronectin [16]. It also activates a number of MMPs, including MMP-1 and MMP-13, that degrade the ECM proteins and the components of the basal membrane, e.g., Collagen I, Collagen II, Collagen III, Collagen IV, and Vitronectin [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28].

The proteolytic activity of Plasmin is regulated by plasminogen activator inhibitors, such as Serpin peptidase inhibitor (PAI1) and Serpin peptidase inhibitor member 2 (SERPINE2) that bind covalently to PLAU and PLAT and inhibit their catalytic activity [29], [30], [31], [32].

In addition to the proteolytic function, the tissue-type PLAU plays an important role in the cell migration and tissue remodeling. It binds to its receptor PLAUR and mediates a variety of functions involved in vascular homeostasis, inflammation and tissue repair [33].

Kallikrein 2 and Kallikrein-related peptidase 3 (Kallikrein 3) also cleave Insulin-like growth factor binding protein 4 (IBP4). IBP4 fragments generated by kallikreins lose binding capacity to Insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), thereby increasing bioavailability of IGF-1 and IGF-2. The latter two activate IGF-1 receptor that is involved in the signaling implicated with cell growth, proliferation and survival [12], [34].

Cell surface heparan sulfate proteoglycan CD44 recruits proteolytically active Matrilysin (MMP-7) and precursor of Heparin-binding EGF-like growth factor (HB-EGF) to form a complex on the cell surface. Matrilysin (MMP-7) cleaves the membrane-bound HB-EGF precursor, thus releasing active HB-EGF. The latter then activates its receptors, Epidermal growth factor receptor (EGFR) and v-Erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4), thereby leading to cell proliferation, cell survival and tissue remodeling [35], [36].

ECM components regulate cell motility and adhesion in response to the external environmental processes, such as ECM remodeling [37]. For example, Collagen IV, the component of the basement membrane, binds to Alpha-1/beta-1 integrin. Fibronectin binds to Alpha-5/beta-1 integrin. This induces both cell adhesion, and intracellular signaling [38], [39], [40], [41], [42], [43], [44]. PLAUR binds to Alpha-5/beta-1 integrin and alters its conformation to promote ligand-binding affinity [45].

Cell surface heparan sulfate proteoglycans, CD44 and Syndecan-2, bind ECM chondroitin sulfate proteoglycan Versican and ECM protein Laminin, alpha 4 (LAMA4), respectively. CD44 and Syndecan-2 are implicated in the formation of a direct link between ECM and cortical cytoplasm via association with the actin cytoskeleton binding proteins Ezrin and Moesin [46], [47], [48], [49], [50], [51].

The action of MMPs is not restricted to degradation of the extracellular matrix; these proteases can modify many non-matrix substrates, such as cytokines and chemokines. For example, MMP-9 potentiates Interleukin-8 (IL-8) activity by aminoterminal processing. IL-8 signaling via Interleukin 8 receptor alpha (IL8RA) leads to the activation of neutrophils and chemotaxis [52], [53].

References:

  1. Raffetto JD, Khalil RA
    Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochemical pharmacology 2008 Jan 15;75(2):346-59
  2. Verstappen J, Von den Hoff JW
    Tissue inhibitors of metalloproteinases (TIMPs): their biological functions and involvement in oral disease. Journal of dental research 2006 Dec;85(12):1074-84
  3. Hannas AR, Pereira JC, Granjeiro JM, Tjaderhane L
    The role of matrix metalloproteinases in the oral environment. Acta odontologica Scandinavica 2007 Feb;65(1):1-13
  4. Verma RP, Hansch C
    Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs. Bioorganic & medicinal chemistry 2007 Mar 15;15(6):2223-68
  5. Bejarano PA, Noelken ME, Suzuki K, Hudson BG, Nagase H
    Degradation of basement membranes by human matrix metalloproteinase 3 (stromelysin). The Biochemical journal 1988 Dec 1;256(2):413-9
  6. Sage EH, Reed M, Funk SE, Truong T, Steadele M, Puolakkainen P, Maurice DH, Bassuk JA
    Cleavage of the matricellular protein SPARC by matrix metalloproteinase 3 produces polypeptides that influence angiogenesis. The Journal of biological chemistry 2003 Sep 26;278(39):37849-57
  7. Cummins PM, von Offenberg Sweeney N, Killeen MT, Birney YA, Redmond EM, Cahill PA
    Cyclic strain-mediated matrix metalloproteinase regulation within the vascular endothelium: a force to be reckoned with. American journal of physiology. Heart and circulatory physiology 2007 Jan;292(1):H28-42
  8. Rechardt O, Elomaa O, Vaalamo M, Paakkonen K, Jahkola T, Hook-Nikanne J, Hembry RM, Hakkinen L, Kere J, Saarialho-Kere U
    Stromelysin-2 is upregulated during normal wound repair and is induced by cytokines. The Journal of investigative dermatology 2000 Nov;115(5):778-87
  9. Zucker S, Pei D, Cao J, Lopez-Otin C
    Membrane type-matrix metalloproteinases (MT-MMP). Current topics in developmental biology 2003;54:1-74
  10. Desrivieres S, Lu H, Peyri N, Soria C, Legrand Y, Menashi S
    Activation of the 92 kDa type IV collagenase by tissue kallikrein. Journal of cellular physiology 1993 Dec;157(3):587-93
  11. Passi A, Negrini D, Albertini R, Miserocchi G, De Luca G
    The sensitivity of versican from rabbit lung to gelatinase A (MMP-2) and B (MMP-9) and its involvement in the development of hydraulic lung edema. FEBS letters 1999 Jul 30;456(1):93-6
  12. Borgo?o CA, Diamandis EP
    The emerging roles of human tissue kallikreins in cancer. Nature reviews. Cancer 2004 Nov;4(11):876-90
  13. Pearce WH, Shively VP
    Abdominal aortic aneurysm as a complex multifactorial disease: interactions of polymorphisms of inflammatory genes, features of autoimmunity, and current status of MMPs. Annals of the New York Academy of Sciences 2006 Nov;1085:117-32
  14. Frenette G, Tremblay RR, Lazure C, Dube JY
    Prostatic kallikrein hK2, but not prostate-specific antigen (hK3), activates single-chain urokinase-type plasminogen activator. International journal of cancer. Journal international du cancer 1997 May 29;71(5):897-9
  15. Cesarman-Maus G, Hajjar KA
    Molecular mechanisms of fibrinolysis. British journal of haematology 2005 May;129(3):307-21
  16. Bonnefoy A, Legrand C
    Proteolysis of subendothelial adhesive glycoproteins (fibronectin, thrombospondin, and von Willebrand factor) by plasmin, leukocyte cathepsin G, and elastase. Thrombosis research 2000 May 15;98(4):323-32
  17. Imai K, Shikata H, Okada Y
    Degradation of vitronectin by matrix metalloproteinases-1, -2, -3, -7 and -9. FEBS letters 1995 Aug 7;369(2-3):249-51
  18. Knauper V, Lopez-Otin C, Smith B, Knight G, Murphy G
    Biochemical characterization of human collagenase-3. The Journal of biological chemistry 1996 Jan 19;271(3):1544-50
  19. Shapiro SD
    Matrix metalloproteinase degradation of extracellular matrix: biological consequences. Current opinion in cell biology 1998 Oct;10(5):602-8
  20. Netzel-Arnett S, Mitola DJ, Yamada SS, Chrysovergis K, Holmbeck K, Birkedal-Hansen H, Bugge TH
    Collagen dissolution by keratinocytes requires cell surface plasminogen activation and matrix metalloproteinase activity. The Journal of biological chemistry 2002 Nov 22;277(47):45154-61
  21. Zucker S, Vacirca J
    Role of matrix metalloproteinases (MMPs) in colorectal cancer. Cancer metastasis reviews 2004 Jan-Jun;23(1-2):101-17
  22. Zijlstra A, Aimes RT, Zhu D, Regazzoni K, Kupriyanova T, Seandel M, Deryugina EI, Quigley JP
    Collagenolysis-dependent angiogenesis mediated by matrix metalloproteinase-13 (collagenase-3). The Journal of biological chemistry 2004 Jun 25;279(26):27633-45
  23. Pardo A, Selman M
    MMP-1: the elder of the family. The international journal of biochemistry & cell biology 2005 Feb;37(2):283-8
  24. Jinnin M, Ihn H, Mimura Y, Asano Y, Yamane K, Tamaki K
    Effects of hepatocyte growth factor on the expression of type I collagen and matrix metalloproteinase-1 in normal and scleroderma dermal fibroblasts. The Journal of investigative dermatology 2005 Feb;124(2):324-30
  25. Morgan H, Hill PA
    Human breast cancer cell-mediated bone collagen degradation requires plasminogen activation and matrix metalloproteinase activity. Cancer cell international 2005 Feb 8;5(1):1
  26. Roy R, Zhang B, Moses MA
    Making the cut: protease-mediated regulation of angiogenesis. Experimental cell research 2006 Mar 10;312(5):608-22
  27. Ra HJ, Parks WC
    Control of matrix metalloproteinase catalytic activity. Matrix biology : journal of the International Society for Matrix Biology 2007 Oct;26(8):587-96
  28. Sengupta N, MacDonald TT
    The role of matrix metalloproteinases in stromal/epithelial interactions in the gut. Physiology (Bethesda, Md.) 2007 Dec;22:401-9
  29. Donovan FM, Vaughan PJ, Cunningham DD
    Regulation of protease nexin-1 target protease specificity by collagen type IV. The Journal of biological chemistry 1994 Jun 24;269(25):17199-205
  30. Conese M, Olson D, Blasi F
    Protease nexin-1-urokinase complexes are internalized and degraded through a mechanism that requires both urokinase receptor and alpha 2-macroglobulin receptor. The Journal of biological chemistry 1994 Jul 8;269(27):17886-92
  31. Mulligan-Kehoe MJ, Wagner R, Wieland C, Powell R
    A truncated plasminogen activator inhibitor-1 protein induces and inhibits angiostatin (kringles 1-3), a plasminogen cleavage product. The Journal of biological chemistry 2001 Mar 16;276(11):8588-96
  32. Perron MJ, Blouse GE, Shore JD
    Distortion of the catalytic domain of tissue-type plasminogen activator by plasminogen activator inhibitor-1 coincides with the formation of stable serpin-proteinase complexes. The Journal of biological chemistry 2003 Nov 28;278(48):48197-203
  33. Stepanova VV, Tkachuk VA
    Urokinase as a multidomain protein and polyfunctional cell regulator. Biochemistry. Biokhimiia 2002 Jan;67(1):109-18
  34. Rehault S, Monget P, Mazerbourg S, Tremblay R, Gutman N, Gauthier F, Moreau T
    Insulin-like growth factor binding proteins (IGFBPs) as potential physiological substrates for human kallikreins hK2 and hK3. European journal of biochemistry / FEBS 2001 May;268(10):2960-8
  35. Yu WH, Woessner JF Jr, McNeish JD, Stamenkovic I
    CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes & development 2002 Feb 1;16(3):307-23
  36. Ii M, Yamamoto H, Adachi Y, Maruyama Y, Shinomura Y
    Role of matrix metalloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth, and angiogenesis. Experimental biology and medicine (Maywood, N.J.) 2006 Jan;231(1):20-7
  37. Morgan MR, Humphries MJ, Bass MD
    Synergistic control of cell adhesion by integrins and syndecans. Nature reviews. Molecular cell biology 2007 Dec;8(12):957-69
  38. Fleischmajer R, Perlish JS, MacDonald ED 2nd, Schechter A, Murdoch AD, Iozzo RV, Yamada Y
    There is binding of collagen IV to beta 1 integrin during early skin basement membrane assembly. Annals of the New York Academy of Sciences 1998 Oct 23;857:212-27
  39. Loeser RF
    Chondrocyte integrin expression and function. Biorheology 2000;37(1-2):109-16
  40. Chavakis T, Cines DB, Rhee JS, Liang OD, Schubert U, Hammes HP, Higazi AA, Nawroth PP, Preissner KT, Bdeir K
    Regulation of neovascularization by human neutrophil peptides (alpha-defensins): a link between inflammation and angiogenesis. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2004 Aug;18(11):1306-8
  41. Korah R, Boots M, Wieder R
    Integrin alpha5beta1 promotes survival of growth-arrested breast cancer cells: an in vitro paradigm for breast cancer dormancy in bone marrow. Cancer research 2004 Jul 1;64(13):4514-22
  42. Kaido T, Yebra M, Cirulli V, Montgomery AM
    Regulation of human beta-cell adhesion, motility, and insulin secretion by collagen IV and its receptor alpha1beta1. The Journal of biological chemistry 2004 Dec 17;279(51):53762-9
  43. Givant-Horwitz V, Davidson B, Reich R
    Laminin-induced signaling in tumor cells. Cancer letters 2005 Jun 1;223(1):1-10
  44. Danen EH, van Rheenen J, Franken W, Huveneers S, Sonneveld P, Jalink K, Sonnenberg A
    Integrins control motile strategy through a Rho-cofilin pathway. The Journal of cell biology 2005 May 9;169(3):515-26
  45. Wei Y, Czekay RP, Robillard L, Kugler MC, Zhang F, Kim KK, Xiong JP, Humphries MJ, Chapman HA
    Regulation of alpha5beta1 integrin conformation and function by urokinase receptor binding. The Journal of cell biology 2005 Jan 31;168(3):501-11
  46. Hirao M, Sato N, Kondo T, Yonemura S, Monden M, Sasaki T, Takai Y, Tsukita S, Tsukita S
    Regulation mechanism of ERM (ezrin/radixin/moesin) protein/plasma membrane association: possible involvement of phosphatidylinositol turnover and Rho-dependent signaling pathway. The Journal of cell biology 1996 Oct;135(1):37-51
  47. Granes F, Urena JM, Rocamora N, Vilaro S
    Ezrin links syndecan-2 to the cytoskeleton. Journal of cell science 2000 Apr;113 ( Pt 7):1267-76
  48. Kawashima H, Hirose M, Hirose J, Nagakubo D, Plaas AH, Miyasaka M
    Binding of a large chondroitin sulfate/dermatan sulfate proteoglycan, versican, to L-selectin, P-selectin, and CD44. The Journal of biological chemistry 2000 Nov 10;275(45):35448-56
  49. Matsuura H, Momota Y, Murata K, Matsushima H, Suzuki N, Nomizu M, Shinkai H, Utani A
    Localization of the laminin alpha4 chain in the skin and identification of a heparin-dependent cell adhesion site within the laminin alpha4 chain C-terminal LG4 module. The Journal of investigative dermatology 2004 Mar;122(3):614-20
  50. Essner JJ, Chen E, Ekker SC
    Syndecan-2. The international journal of biochemistry & cell biology 2006 Feb;38(2):152-6
  51. Christofori G
    New signals from the invasive front. Nature 2006 May 25;441(7092):444-50
  52. Van den Steen PE, Proost P, Wuyts A, Van Damme J, Opdenakker G
    Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood 2000 Oct 15;96(8):2673-81
  53. Wolf M, Albrecht S, Marki C
    Proteolytic processing of chemokines: implications in physiological and pathological conditions. The international journal of biochemistry & cell biology 2008;40(6-7):1185-98

  1. Raffetto JD, Khalil RA
    Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochemical pharmacology 2008 Jan 15;75(2):346-59
  2. Verstappen J, Von den Hoff JW
    Tissue inhibitors of metalloproteinases (TIMPs): their biological functions and involvement in oral disease. Journal of dental research 2006 Dec;85(12):1074-84
  3. Hannas AR, Pereira JC, Granjeiro JM, Tjaderhane L
    The role of matrix metalloproteinases in the oral environment. Acta odontologica Scandinavica 2007 Feb;65(1):1-13
  4. Verma RP, Hansch C
    Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs. Bioorganic & medicinal chemistry 2007 Mar 15;15(6):2223-68
  5. Bejarano PA, Noelken ME, Suzuki K, Hudson BG, Nagase H
    Degradation of basement membranes by human matrix metalloproteinase 3 (stromelysin). The Biochemical journal 1988 Dec 1;256(2):413-9
  6. Sage EH, Reed M, Funk SE, Truong T, Steadele M, Puolakkainen P, Maurice DH, Bassuk JA
    Cleavage of the matricellular protein SPARC by matrix metalloproteinase 3 produces polypeptides that influence angiogenesis. The Journal of biological chemistry 2003 Sep 26;278(39):37849-57
  7. Cummins PM, von Offenberg Sweeney N, Killeen MT, Birney YA, Redmond EM, Cahill PA
    Cyclic strain-mediated matrix metalloproteinase regulation within the vascular endothelium: a force to be reckoned with. American journal of physiology. Heart and circulatory physiology 2007 Jan;292(1):H28-42
  8. Rechardt O, Elomaa O, Vaalamo M, Paakkonen K, Jahkola T, Hook-Nikanne J, Hembry RM, Hakkinen L, Kere J, Saarialho-Kere U
    Stromelysin-2 is upregulated during normal wound repair and is induced by cytokines. The Journal of investigative dermatology 2000 Nov;115(5):778-87
  9. Zucker S, Pei D, Cao J, Lopez-Otin C
    Membrane type-matrix metalloproteinases (MT-MMP). Current topics in developmental biology 2003;54:1-74
  10. Desrivieres S, Lu H, Peyri N, Soria C, Legrand Y, Menashi S
    Activation of the 92 kDa type IV collagenase by tissue kallikrein. Journal of cellular physiology 1993 Dec;157(3):587-93
  11. Passi A, Negrini D, Albertini R, Miserocchi G, De Luca G
    The sensitivity of versican from rabbit lung to gelatinase A (MMP-2) and B (MMP-9) and its involvement in the development of hydraulic lung edema. FEBS letters 1999 Jul 30;456(1):93-6
  12. Borgo?o CA, Diamandis EP
    The emerging roles of human tissue kallikreins in cancer. Nature reviews. Cancer 2004 Nov;4(11):876-90
  13. Pearce WH, Shively VP
    Abdominal aortic aneurysm as a complex multifactorial disease: interactions of polymorphisms of inflammatory genes, features of autoimmunity, and current status of MMPs. Annals of the New York Academy of Sciences 2006 Nov;1085:117-32
  14. Frenette G, Tremblay RR, Lazure C, Dube JY
    Prostatic kallikrein hK2, but not prostate-specific antigen (hK3), activates single-chain urokinase-type plasminogen activator. International journal of cancer. Journal international du cancer 1997 May 29;71(5):897-9
  15. Cesarman-Maus G, Hajjar KA
    Molecular mechanisms of fibrinolysis. British journal of haematology 2005 May;129(3):307-21
  16. Bonnefoy A, Legrand C
    Proteolysis of subendothelial adhesive glycoproteins (fibronectin, thrombospondin, and von Willebrand factor) by plasmin, leukocyte cathepsin G, and elastase. Thrombosis research 2000 May 15;98(4):323-32
  17. Imai K, Shikata H, Okada Y
    Degradation of vitronectin by matrix metalloproteinases-1, -2, -3, -7 and -9. FEBS letters 1995 Aug 7;369(2-3):249-51
  18. Knauper V, Lopez-Otin C, Smith B, Knight G, Murphy G
    Biochemical characterization of human collagenase-3. The Journal of biological chemistry 1996 Jan 19;271(3):1544-50
  19. Shapiro SD
    Matrix metalloproteinase degradation of extracellular matrix: biological consequences. Current opinion in cell biology 1998 Oct;10(5):602-8
  20. Netzel-Arnett S, Mitola DJ, Yamada SS, Chrysovergis K, Holmbeck K, Birkedal-Hansen H, Bugge TH
    Collagen dissolution by keratinocytes requires cell surface plasminogen activation and matrix metalloproteinase activity. The Journal of biological chemistry 2002 Nov 22;277(47):45154-61
  21. Zucker S, Vacirca J
    Role of matrix metalloproteinases (MMPs) in colorectal cancer. Cancer metastasis reviews 2004 Jan-Jun;23(1-2):101-17
  22. Zijlstra A, Aimes RT, Zhu D, Regazzoni K, Kupriyanova T, Seandel M, Deryugina EI, Quigley JP
    Collagenolysis-dependent angiogenesis mediated by matrix metalloproteinase-13 (collagenase-3). The Journal of biological chemistry 2004 Jun 25;279(26):27633-45
  23. Pardo A, Selman M
    MMP-1: the elder of the family. The international journal of biochemistry & cell biology 2005 Feb;37(2):283-8
  24. Jinnin M, Ihn H, Mimura Y, Asano Y, Yamane K, Tamaki K
    Effects of hepatocyte growth factor on the expression of type I collagen and matrix metalloproteinase-1 in normal and scleroderma dermal fibroblasts. The Journal of investigative dermatology 2005 Feb;124(2):324-30
  25. Morgan H, Hill PA
    Human breast cancer cell-mediated bone collagen degradation requires plasminogen activation and matrix metalloproteinase activity. Cancer cell international 2005 Feb 8;5(1):1
  26. Roy R, Zhang B, Moses MA
    Making the cut: protease-mediated regulation of angiogenesis. Experimental cell research 2006 Mar 10;312(5):608-22
  27. Ra HJ, Parks WC
    Control of matrix metalloproteinase catalytic activity. Matrix biology : journal of the International Society for Matrix Biology 2007 Oct;26(8):587-96
  28. Sengupta N, MacDonald TT
    The role of matrix metalloproteinases in stromal/epithelial interactions in the gut. Physiology (Bethesda, Md.) 2007 Dec;22:401-9
  29. Donovan FM, Vaughan PJ, Cunningham DD
    Regulation of protease nexin-1 target protease specificity by collagen type IV. The Journal of biological chemistry 1994 Jun 24;269(25):17199-205
  30. Conese M, Olson D, Blasi F
    Protease nexin-1-urokinase complexes are internalized and degraded through a mechanism that requires both urokinase receptor and alpha 2-macroglobulin receptor. The Journal of biological chemistry 1994 Jul 8;269(27):17886-92
  31. Mulligan-Kehoe MJ, Wagner R, Wieland C, Powell R
    A truncated plasminogen activator inhibitor-1 protein induces and inhibits angiostatin (kringles 1-3), a plasminogen cleavage product. The Journal of biological chemistry 2001 Mar 16;276(11):8588-96
  32. Perron MJ, Blouse GE, Shore JD
    Distortion of the catalytic domain of tissue-type plasminogen activator by plasminogen activator inhibitor-1 coincides with the formation of stable serpin-proteinase complexes. The Journal of biological chemistry 2003 Nov 28;278(48):48197-203
  33. Stepanova VV, Tkachuk VA
    Urokinase as a multidomain protein and polyfunctional cell regulator. Biochemistry. Biokhimiia 2002 Jan;67(1):109-18
  34. Rehault S, Monget P, Mazerbourg S, Tremblay R, Gutman N, Gauthier F, Moreau T
    Insulin-like growth factor binding proteins (IGFBPs) as potential physiological substrates for human kallikreins hK2 and hK3. European journal of biochemistry / FEBS 2001 May;268(10):2960-8
  35. Yu WH, Woessner JF Jr, McNeish JD, Stamenkovic I
    CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes & development 2002 Feb 1;16(3):307-23
  36. Ii M, Yamamoto H, Adachi Y, Maruyama Y, Shinomura Y
    Role of matrix metalloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth, and angiogenesis. Experimental biology and medicine (Maywood, N.J.) 2006 Jan;231(1):20-7
  37. Morgan MR, Humphries MJ, Bass MD
    Synergistic control of cell adhesion by integrins and syndecans. Nature reviews. Molecular cell biology 2007 Dec;8(12):957-69
  38. Fleischmajer R, Perlish JS, MacDonald ED 2nd, Schechter A, Murdoch AD, Iozzo RV, Yamada Y
    There is binding of collagen IV to beta 1 integrin during early skin basement membrane assembly. Annals of the New York Academy of Sciences 1998 Oct 23;857:212-27
  39. Loeser RF
    Chondrocyte integrin expression and function. Biorheology 2000;37(1-2):109-16
  40. Chavakis T, Cines DB, Rhee JS, Liang OD, Schubert U, Hammes HP, Higazi AA, Nawroth PP, Preissner KT, Bdeir K
    Regulation of neovascularization by human neutrophil peptides (alpha-defensins): a link between inflammation and angiogenesis. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2004 Aug;18(11):1306-8
  41. Korah R, Boots M, Wieder R
    Integrin alpha5beta1 promotes survival of growth-arrested breast cancer cells: an in vitro paradigm for breast cancer dormancy in bone marrow. Cancer research 2004 Jul 1;64(13):4514-22
  42. Kaido T, Yebra M, Cirulli V, Montgomery AM
    Regulation of human beta-cell adhesion, motility, and insulin secretion by collagen IV and its receptor alpha1beta1. The Journal of biological chemistry 2004 Dec 17;279(51):53762-9
  43. Givant-Horwitz V, Davidson B, Reich R
    Laminin-induced signaling in tumor cells. Cancer letters 2005 Jun 1;223(1):1-10
  44. Danen EH, van Rheenen J, Franken W, Huveneers S, Sonneveld P, Jalink K, Sonnenberg A
    Integrins control motile strategy through a Rho-cofilin pathway. The Journal of cell biology 2005 May 9;169(3):515-26
  45. Wei Y, Czekay RP, Robillard L, Kugler MC, Zhang F, Kim KK, Xiong JP, Humphries MJ, Chapman HA
    Regulation of alpha5beta1 integrin conformation and function by urokinase receptor binding. The Journal of cell biology 2005 Jan 31;168(3):501-11
  46. Hirao M, Sato N, Kondo T, Yonemura S, Monden M, Sasaki T, Takai Y, Tsukita S, Tsukita S
    Regulation mechanism of ERM (ezrin/radixin/moesin) protein/plasma membrane association: possible involvement of phosphatidylinositol turnover and Rho-dependent signaling pathway. The Journal of cell biology 1996 Oct;135(1):37-51
  47. Granes F, Urena JM, Rocamora N, Vilaro S
    Ezrin links syndecan-2 to the cytoskeleton. Journal of cell science 2000 Apr;113 ( Pt 7):1267-76
  48. Kawashima H, Hirose M, Hirose J, Nagakubo D, Plaas AH, Miyasaka M
    Binding of a large chondroitin sulfate/dermatan sulfate proteoglycan, versican, to L-selectin, P-selectin, and CD44. The Journal of biological chemistry 2000 Nov 10;275(45):35448-56
  49. Matsuura H, Momota Y, Murata K, Matsushima H, Suzuki N, Nomizu M, Shinkai H, Utani A
    Localization of the laminin alpha4 chain in the skin and identification of a heparin-dependent cell adhesion site within the laminin alpha4 chain C-terminal LG4 module. The Journal of investigative dermatology 2004 Mar;122(3):614-20
  50. Essner JJ, Chen E, Ekker SC
    Syndecan-2. The international journal of biochemistry & cell biology 2006 Feb;38(2):152-6
  51. Christofori G
    New signals from the invasive front. Nature 2006 May 25;441(7092):444-50
  52. Van den Steen PE, Proost P, Wuyts A, Van Damme J, Opdenakker G
    Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood 2000 Oct 15;96(8):2673-81
  53. Wolf M, Albrecht S, Marki C
    Proteolytic processing of chemokines: implications in physiological and pathological conditions. The international journal of biochemistry & cell biology 2008;40(6-7):1185-98

Target Details

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