Gemma presents at GRC
On July 18th Gemma Bourne presented her work on TGF-beta processing in a Hot Topic talk at the Gordon Research Conference on Proprotein Processing, Trafficking & Secretion.
Gemma described the development and characterisation of an assay to measure furin activity in cells, which she is using to investigate how changes in furin activity affect the proteolytic processing of proTGF-beta. Until recently, this processing step has been considered to occur intracellularly and in a constitutive manner. However, there are several reports that expression of furin, the main protease responsible for proTGF-beta processing, can be induced in response to environmental cues, including stimulation by active TGF-beta. In the absence of an assay sensitive enough to detect endogenous furin, these studies have been limited to analysis of mRNA expression, but have important implications; Gemma has shown that the extent of processing of proTGF-beta1 differs between cell types, which may reflect differences in furin activity.
Gemma went on to report that the extent of proTGF-beta1 processing does indeed correlate with the level of cellular furin activity quantified using the assay. Further more, she was able to show that stimulation with active TGF-beta1 induced not only an increase in furin mRNA but also increased furin activity, demonstrating for the first time induction of furin at the activity level. These findings, summarised in her poster, support the hypothesis that proteolytic processing is not merely a constitutive step in the maturation of TGF-beta, but is an important step for regulation of its activity.
The substrates of furin and the other proprotein convertases comprise a broad range of cellular proteins, including enzymes, cytokines and receptors, and so regulating proprotein convertase activity may be key to co-ordinating the activity of many effector proteins simultaneously. As such, the proprotein convertases may occupy a central position in many important homeostatic and pathological processes, including tumourigenesis and atherogenesis. In fact, many of the proprotein convertase substrates are represented in processes that contribute to the cluster of risk factors that comprise the Metabolic Syndrome; obesity, dyslipidemia, hypertension and subclinical inflammation, which are associated with atherosclerosis and type II diabetes. This lead to the proposal by David Grainger that a reduction in the activity of the proprotein convertases could affect the levels of the active forms of their substrates, and so cause and/or perpetuate the characteristic symptoms of the Metabolic Syndrome (BioEssays. 28: 629). Work is still ongoing to test this exciting hypothesis, with the aim of identifying a novel range of targets for therapeutic intervention.
Gemma described the development and characterisation of an assay to measure furin activity in cells, which she is using to investigate how changes in furin activity affect the proteolytic processing of proTGF-beta. Until recently, this processing step has been considered to occur intracellularly and in a constitutive manner. However, there are several reports that expression of furin, the main protease responsible for proTGF-beta processing, can be induced in response to environmental cues, including stimulation by active TGF-beta. In the absence of an assay sensitive enough to detect endogenous furin, these studies have been limited to analysis of mRNA expression, but have important implications; Gemma has shown that the extent of processing of proTGF-beta1 differs between cell types, which may reflect differences in furin activity.
Gemma went on to report that the extent of proTGF-beta1 processing does indeed correlate with the level of cellular furin activity quantified using the assay. Further more, she was able to show that stimulation with active TGF-beta1 induced not only an increase in furin mRNA but also increased furin activity, demonstrating for the first time induction of furin at the activity level. These findings, summarised in her poster, support the hypothesis that proteolytic processing is not merely a constitutive step in the maturation of TGF-beta, but is an important step for regulation of its activity.
The substrates of furin and the other proprotein convertases comprise a broad range of cellular proteins, including enzymes, cytokines and receptors, and so regulating proprotein convertase activity may be key to co-ordinating the activity of many effector proteins simultaneously. As such, the proprotein convertases may occupy a central position in many important homeostatic and pathological processes, including tumourigenesis and atherogenesis. In fact, many of the proprotein convertase substrates are represented in processes that contribute to the cluster of risk factors that comprise the Metabolic Syndrome; obesity, dyslipidemia, hypertension and subclinical inflammation, which are associated with atherosclerosis and type II diabetes. This lead to the proposal by David Grainger that a reduction in the activity of the proprotein convertases could affect the levels of the active forms of their substrates, and so cause and/or perpetuate the characteristic symptoms of the Metabolic Syndrome (BioEssays. 28: 629). Work is still ongoing to test this exciting hypothesis, with the aim of identifying a novel range of targets for therapeutic intervention.