The Biochemistry and Regulation of S100A10: A Multifunctional Plasminogen Receptor Involved in Oncogenesis

Abstract

The plasminogen receptors mediate the production and localization to the cell surface of the broad spectrum proteinase, plasmin. S100A10 is a key regulator of cellular plasmin production and may account for as much as 50% of cellular plasmin generation. In parallel to plasminogen, the plasminogen-binding site on S100A10 is highly conserved from mammals to fish. S100A10 is constitutively expressed in many cells and is also induced by many diverse factors and physiological stimuli including dexamethasone, epidermal growth factor, transforming growth factor-α, interferon-γ, nerve growth factor, keratinocyte growth factor, retinoic acid, and thrombin. Therefore, S100A10 is utilized by cells to regulate plasmin proteolytic activity in response to a wide diversity of physiological stimuli. The expression of the oncogenes, PML-RARα and KRas, also stimulates the levels of S100A10, suggesting a role for S100A10 in pathophysiological processes such as in the oncogenic-mediated increases in plasmin production. The S100A10-null mouse model system has established the critical role that S100A10 plays as a regulator of fibrinolysis and oncogenesis. S100A10 plays two major roles in oncogenesis, first as a regulator of cancer cell invasion and metastasis and secondly as a regulator of the recruitment of tumor-associated cells, such as macrophages, to the tumor site.

New Insights into the Role of Plg-RKT in Macrophage Recruitment

“…Physiologic and pathophysiologic processes with plasmin-dependent cell migration as a central feature include inflammation (Ploplis, French, Carmeliet, Collen & Plow, 1998; Plow, Ploplis, Busuttil, Carmeliet & Collen, 1999; Busuttil, Ploplis, Castellino, Tang, Eaton & Plow, 2004), wound healing (Romer, Bugge, Pyke, Lund, Flick, Degen & Dano, 1996; Creemers, Cleutjens, Smits, Heymans, Moons, Collen, Daemen & Carmeliet, 2000), oncogenesis (Madureira, Hill, Miller, Giacomantonio, Lee & Waisman, 2011a; Madureira, O’Connell, Surette, Miller & Waisman, 2012), metastasis (Ranson, Andronicos, O’Mullane & Baker, 1998; Palumbo, Talmage, Liu, La Jeunesse, Witte & Degen, 2003), myogenesis, and muscle regeneration (Suelves, Lopez-Alemany, Lluis, Aniorte, Serrano, Parra, Carmeliet & Munoz-Canoves, 2002; Lopez-Alemany, Suelves & Munoz-Canoves, 2003; Lopez-Alemany, Suelves, Diaz-Ramos, Vidal & Munoz-Canoves, 2005). Cell surface plasmin also participates in neurite outgrowth (Jacovina, Zhong, Khazanova, Lev, Deora & Hajjar, 2001; Gutierrez-Fernandez, Gingles, Bai, Castellino, Parmer & Miles, 2009), and prohormone processing (Parmer, Mahata, Gong, Mahata, Jiang, O’Connor, Xi & Miles, 2000; Jiang, Taupenot, Mahata, Mahata, O’Connor, Miles & Parmer, 2001; Jiang, Yasothornsrikul, Taupenot, Miles & Parmer, 2002; Bai, Nangia & Parmer, 2012).…”

“…This results in association of the broad spectrum proteolytic activity of plasmin with the cell surface leading to a wide array of physiological and pathological sequelae. Physiologic and pathophysiologic processes with plasmin-dependent cell migration as a central feature include inflammation (Ploplis et al, 1998; Plow et al, 1999; Busuttil et al, 2004), wound healing (Romer et al, 1996; Creemers et al, 2000), oncogenesis (Madureira et al, 2011a; Madureira et al, 2012), metastasis (Ranson et al, 1998; Palumbo et al, 2003), myogenesis, and muscle regeneration (Suelves et al, 2002; Lopez-Alemany et al, 2003; Lopez-Alemany et al, 2005). Cell surface plasmin also participates in neurite outgrowth (Jacovina et al, 2001; Gutierrez-Fernandez et al, 2009), and prohormone processing (Parmer et al, 2000; Jiang et al, 2001; Jiang et al, 2002; Bai et al, 2012).…”

Annexin A2 and S100A10 Regulate Human Papillomavirus Type 16 Entry and Intracellular Trafficking in Human Keratinocytes

“…The A2t at the cell surface is a prominent plasminogen receptor and activator; other known actions of S100A10 that may or may not be separate from A2t interactions involve immune cells and brain functions (47). S100A10 appears to be required for AnxA2 activities at the cell surface in cultured cells, and S100A10 is undetectable unless AnxA2 is also expressed (48).…”

Annexin A2 and S100A10 in the mammalian oviduct

“…It is also the most frequent binding partner of AnxA2, described more than 30 years ago (Erikson et al, 1984). Extracellularly, AnxA2's largest studied function is as a cell surface protector for the plasminogen receptor S100A10 (reviewed in Madureira et al, 2012). In addition, AnxA2 also interacts with extracellular receptors such as Toll-Like receptor 4 (TLR4) (Swisher et al, 2010) and ligands such as gastrin (Singh et al, 2007).…”