title: Splice variants of Tissue Factor and integrin-mediated signaling.
abstract: Full-length Tissue Factor (flTF) - the obligatory co-factor for the serine protease (factor) VII/VIIa - serves as the initiator of blood coagulation. The flTF/VIIa complex triggers a sequence of proteolytic events that lead to the formation of a hemostatic plug. Aside from hemostatic maintenance, flTF can contribute to thrombogenesis in some settings. The proteolytic properties of the flTF/VIIa complex (as well as the flTF/VIIa/Xa complex) account for non-hemostatic functions of flTF, largely exerted through activation of intracellular signaling via Protease Activated Receptors (PARs). The flTF-PAR nexus impacts several kinases highly significant in the pathobiology of cancer and cardiovascular disease. Over the past decade, many advances have been made in the understanding of PAR-mediated functions of flTF, an important highlight of which was the finding that a sub-set of integrins - a diverse family of integral membrane proteins - cross-regulate flTF-elicited signaling. Concomitantly, an alternatively spliced TF form (asTF) was discovered in human and mouse. Initial studies characterizing asTF revealed that it is differentially expressed during development, continuously present in circulating blood and solid tissues, and possesses very low pro-coagulant activity. Hypomorphic nature of asTF's cofactor activity is the source of an ongoing controversy over whether asTF is pro-coagulant, and how it may contribute to hemostatic maintenance and/or its aberrations. Very recently, a novel concept emerged in asTF biology: asTF can evidently trigger intracellular signaling that promotes the formation of new vessels from the existing ones (angiogenesis) and monocyte-endothelial interactions, via interaction with integrins. We provide a brief overview of the fl/asTF-integrin nexus with an emphasis on asTF's non-proteolytic, integrin-mediated biological activity.
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Ramprasad
authors.initials: R
authors.lastname: Srinivasan
authors.forename: Vladimir Y
authors.initials: VY
authors.lastname: Bogdanov
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D015870:Gene Expression; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D020033:Protein Isoforms; D015398:Signal Transduction; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*
chemical_list: D016023:Integrins; D020033:Protein Isoforms; D013925:Thromboplastin