Abstract
BackgroundThe plasminogen (PLG) activation system is composed by a series of serine proteases, inhibitors and several binding proteins, which together control the temporal and spatial generation of the active serine protease plasmin. As this proteolytic system plays a central role in human physiology and pathophysiology it has been extensively studied in mammals. The serine proteases of this system are believed to originate from an ancestral gene by gene duplications followed by domain gains and deletions. However, the identification of ancestral forms in primitive chordates supporting these theories remains elusive. In addition, evolutionary studies of the non-proteolytic members of this system are scarce.ResultsOur phylogenetic analyses place lamprey PLG at the root of the vertebrate PLG-group, while lamprey PLG-related growth factors represent the ancestral forms of the jawed-vertebrate orthologues. Furthermore, we find that the earliest putative orthologue of the PLG activator group is the hyaluronan binding protein 2 (HABP2) gene found in lampreys. The prime plasminogen activators (tissue- and urokinase-type plasminogen activator, tPA and uPA) first occur in cartilaginous fish and phylogenetic analyses confirm that all orthologues identified compose monophyletic groups to their mammalian counterparts. Cartilaginous fishes exhibit the most ancient vitronectin of all vertebrates, while plasminogen activator inhibitor 1 (PAI-1) appears for the first time in cartilaginous fishes and is conserved in the rest of jawed vertebrate clades. PAI-2 appears for the first time in the common ancestor of reptiles and mammals, and represents the latest appearing plasminogen activator inhibitor. Finally, we noted that the urokinase-type plasminogen activator receptor (uPAR)—and three-LU domain containing genes in general—occurred later in evolution and was first detectable after coelacanths.ConclusionsThis study identifies several primitive orthologues of the mammalian plasminogen activation system. These ancestral forms provide clues to the origin and diversification of this enzyme system. Further, the discovery of several members—hitherto unknown in mammals—provide new perspectives on the evolution of this important enzyme system.
Highlights
The plasminogen (PLG) activation system is composed by a series of serine proteases, inhibitors and several binding proteins, which together control the temporal and spatial generation of the active serine protease plasmin
The confinement of urokinase plasminogen activator (uPA)-mediated plasminogen activation to the pericellular compartment is driven by expression of the uPA receptor, which is a glycolipid-anchored membrane receptor [5] composed by three Leukocyte antigen 6 (Ly6)/uPAR or Ly6 antigen/uPAR-like domain (LU) domains [6, 7]—all participating in the assembly of a high-affinity binding site for uPA [8,9,10]. uPAR interacts weakly with the somatomedin-B (SMB) domain of the provisional matrix protein vitronectin (VN) [11, 12], providing an additional layer to the regulation of cell attachment and migration
RNA-seq, de novo assembly and generation of protein sequence database from public repositories Around 617 and 327 million 150 bp paired-end reads were generated from brain, kidney, liver and gonads from African lungfish (Protopterus sp) and pond slider turtle (Trachemys scripta), respectively, while 98 million 150 bp paired-end reads were sequenced from kidney and liver from a cane toad (Rhinella marina)
Summary
The plasminogen (PLG) activation system is composed by a series of serine proteases, inhibitors and several binding proteins, which together control the temporal and spatial generation of the active serine protease plasmin As this proteolytic system plays a central role in human physiology and pathophysiology it has been extensively studied in mammals. UPAR interacts weakly with the somatomedin-B (SMB) domain of the provisional matrix protein vitronectin (VN) [11, 12], providing an additional layer to the regulation of cell attachment and migration This process is under allosteric control by the high-affinity binding of uPA [13, 15, 16]. Only a limited number of studies of this system exist in other vertebrates [23,24,25,26,27,28], they have suggested that the mechanisms for plasminogen activation and inhibition are more complex than the one emerging from merely reconciling observations made in mammals
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