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The pancreatic beta cell surface proteome.

Stützer I, Esterházy D, Stoffel M - Diabetologia (2012)

Bottom Line: Various surface proteins that mediate or affect beta cell endocrine function have been identified, including growth factor and cytokine receptors, transporters, ion channels and proteases, attributing important roles to surface proteins in the adaptive behaviour of beta cells in response to acute and chronic environmental changes.However, the largely unknown composition of the beta cell surface proteome is likely to harbour yet more information about these mechanisms and provide novel points of therapeutic intervention and diagnostic tools.This article will provide an overview of the functional complexity of the beta cell surface proteome and selected surface proteins, outline the mechanisms by which their activity may be modulated, discuss the methods and challenges of comprehensively mapping and studying the beta cell surface proteome, and address the potential of this interesting subproteome for diagnostic and therapeutic applications in human disease.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Systems Biology, HPT E73, ETH Zurich, Wolfgang-Pauli-Str 16, 8093 Zurich, Switzerland.

ABSTRACT
The pancreatic beta cell is responsible for maintaining normoglycaemia by secreting an appropriate amount of insulin according to blood glucose levels. The accurate sensing of the beta cell extracellular environment is therefore crucial to this endocrine function and is transmitted via its cell surface proteome. Various surface proteins that mediate or affect beta cell endocrine function have been identified, including growth factor and cytokine receptors, transporters, ion channels and proteases, attributing important roles to surface proteins in the adaptive behaviour of beta cells in response to acute and chronic environmental changes. However, the largely unknown composition of the beta cell surface proteome is likely to harbour yet more information about these mechanisms and provide novel points of therapeutic intervention and diagnostic tools. This article will provide an overview of the functional complexity of the beta cell surface proteome and selected surface proteins, outline the mechanisms by which their activity may be modulated, discuss the methods and challenges of comprehensively mapping and studying the beta cell surface proteome, and address the potential of this interesting subproteome for diagnostic and therapeutic applications in human disease.

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Related in: MedlinePlus

The three steps to characterising the beta cell surface proteome for diagnostic and therapeutic purposes. (a) Identification of the surface proteome, (b) analysis of its dynamic regulation, (c) assessment of the potential use of individual proteins as biomarkers, imaging tools and drug targets
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Related In: Results  -  Collection


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Fig3: The three steps to characterising the beta cell surface proteome for diagnostic and therapeutic purposes. (a) Identification of the surface proteome, (b) analysis of its dynamic regulation, (c) assessment of the potential use of individual proteins as biomarkers, imaging tools and drug targets

Mentions: What is the promise of a comprehensive beta cell surface map? The main hope is that it will be the gateway to targeting and monitoring the function and mass of a cell type that is scarce in number and otherwise hard to reach. The proteome will fall into two topological categories of useful proteins (Fig. 3): permanently beta cell membrane-associated proteins and shed/secreted proteins. The constitutive surface proteins may, provided they are beta cell-specific or -enriched, serve as drug targets and, in principle, as docking points/antigens for beta cell sorting and imaging. The advantage of targeting surface proteins is not only the likely accessibility of the proteins, but also the fact that very often they are found at the beginning of an amplifying signalling cascade, so that affecting one protein, such as a tyrosine kinase receptor, may have large and pleiotropic cellular effects. The current methods used to sort genetically unmodified beta cells (i.e. no fluorescent protein under a beta cell-specific promoter) are based on the differential autofluorescent properties of these cells compared with the rest of the islet as a result of different ion or metabolite contents [98], and unfortunately, yields, viability and purity are still poor. Imaging techniques, such as positron emission tomography (PET) and MRI can currently only reveal beta cells/islets that have previously been chemically treated ex vivo [99] because of the lack of a suitable antigen and/or antibody that could be coupled to a tracer and used non-invasively. The shed or secreted proteins may be used as indicators of beta cell mass, function or internal state in serum or urine. For example, the cleavage fragment of a structural component of beta cells will roughly correlate with the number of beta cells in the body. Such an accurate marker of beta cell mass is desperately needed to assess and appropriately treat type 1 and type 2 diabetes. At present, the main indicator is plasma insulin, levels of which can be maintained after a beta cell loss of up to 80% via functional compensation by the remaining pool. A stressed beta cell may secrete endoplasmic reticulum stress proteins or autophagosomal or apoptotic proteins that leak through the secretory pathway, and so the overall state of the beta cell could be evaluated. In a more therapy-specific way, the sheddome could also be used to monitor the effectiveness of a beta cell-selective protease inhibitor or islet regeneration/transplantation approaches. The challenge here is not only to find those molecules that are beta cell-enriched or beta cell-specific, but also those that are feasibly detectable by ELISA or other clinically compatible diagnostic techniques. Even without clearance by the kidney or other tissues, it is to be expected that such beta cell-derived proteins will be found in serum only at picograms per millilitre to low nanograms per millilitre levels—given that the concentrations of insulin, the most abundant secreted beta cell protein, lie in the nanogram range and, in comparison, prostate specific antigen (PSA), a secreted serine protease and marker for prostate cancer, is only present at low nanograms per millilitre levels even in cancer positive patients, yet is indicative of an organ that is more than 10 times larger than the entire beta cell pool (an average of 11 g prostate versus 0.8 g beta cells). However, if there is a need there is a way and, depending on the chosen biomarker, amplification methods may be at hand: for example, a hypothetical shed fragment with remaining enzymatic activity may be exploited to design an activity rather than concentration–based detection assay. The numerous potential applications of the beta cell derived surfaceome are thus, paradoxically, tightly linked not only to the importance of this cell but much rather precisely to its low abundance and anatomical remoteness.Fig. 3


The pancreatic beta cell surface proteome.

Stützer I, Esterházy D, Stoffel M - Diabetologia (2012)

The three steps to characterising the beta cell surface proteome for diagnostic and therapeutic purposes. (a) Identification of the surface proteome, (b) analysis of its dynamic regulation, (c) assessment of the potential use of individual proteins as biomarkers, imaging tools and drug targets
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369137&req=5

Fig3: The three steps to characterising the beta cell surface proteome for diagnostic and therapeutic purposes. (a) Identification of the surface proteome, (b) analysis of its dynamic regulation, (c) assessment of the potential use of individual proteins as biomarkers, imaging tools and drug targets
Mentions: What is the promise of a comprehensive beta cell surface map? The main hope is that it will be the gateway to targeting and monitoring the function and mass of a cell type that is scarce in number and otherwise hard to reach. The proteome will fall into two topological categories of useful proteins (Fig. 3): permanently beta cell membrane-associated proteins and shed/secreted proteins. The constitutive surface proteins may, provided they are beta cell-specific or -enriched, serve as drug targets and, in principle, as docking points/antigens for beta cell sorting and imaging. The advantage of targeting surface proteins is not only the likely accessibility of the proteins, but also the fact that very often they are found at the beginning of an amplifying signalling cascade, so that affecting one protein, such as a tyrosine kinase receptor, may have large and pleiotropic cellular effects. The current methods used to sort genetically unmodified beta cells (i.e. no fluorescent protein under a beta cell-specific promoter) are based on the differential autofluorescent properties of these cells compared with the rest of the islet as a result of different ion or metabolite contents [98], and unfortunately, yields, viability and purity are still poor. Imaging techniques, such as positron emission tomography (PET) and MRI can currently only reveal beta cells/islets that have previously been chemically treated ex vivo [99] because of the lack of a suitable antigen and/or antibody that could be coupled to a tracer and used non-invasively. The shed or secreted proteins may be used as indicators of beta cell mass, function or internal state in serum or urine. For example, the cleavage fragment of a structural component of beta cells will roughly correlate with the number of beta cells in the body. Such an accurate marker of beta cell mass is desperately needed to assess and appropriately treat type 1 and type 2 diabetes. At present, the main indicator is plasma insulin, levels of which can be maintained after a beta cell loss of up to 80% via functional compensation by the remaining pool. A stressed beta cell may secrete endoplasmic reticulum stress proteins or autophagosomal or apoptotic proteins that leak through the secretory pathway, and so the overall state of the beta cell could be evaluated. In a more therapy-specific way, the sheddome could also be used to monitor the effectiveness of a beta cell-selective protease inhibitor or islet regeneration/transplantation approaches. The challenge here is not only to find those molecules that are beta cell-enriched or beta cell-specific, but also those that are feasibly detectable by ELISA or other clinically compatible diagnostic techniques. Even without clearance by the kidney or other tissues, it is to be expected that such beta cell-derived proteins will be found in serum only at picograms per millilitre to low nanograms per millilitre levels—given that the concentrations of insulin, the most abundant secreted beta cell protein, lie in the nanogram range and, in comparison, prostate specific antigen (PSA), a secreted serine protease and marker for prostate cancer, is only present at low nanograms per millilitre levels even in cancer positive patients, yet is indicative of an organ that is more than 10 times larger than the entire beta cell pool (an average of 11 g prostate versus 0.8 g beta cells). However, if there is a need there is a way and, depending on the chosen biomarker, amplification methods may be at hand: for example, a hypothetical shed fragment with remaining enzymatic activity may be exploited to design an activity rather than concentration–based detection assay. The numerous potential applications of the beta cell derived surfaceome are thus, paradoxically, tightly linked not only to the importance of this cell but much rather precisely to its low abundance and anatomical remoteness.Fig. 3

Bottom Line: Various surface proteins that mediate or affect beta cell endocrine function have been identified, including growth factor and cytokine receptors, transporters, ion channels and proteases, attributing important roles to surface proteins in the adaptive behaviour of beta cells in response to acute and chronic environmental changes.However, the largely unknown composition of the beta cell surface proteome is likely to harbour yet more information about these mechanisms and provide novel points of therapeutic intervention and diagnostic tools.This article will provide an overview of the functional complexity of the beta cell surface proteome and selected surface proteins, outline the mechanisms by which their activity may be modulated, discuss the methods and challenges of comprehensively mapping and studying the beta cell surface proteome, and address the potential of this interesting subproteome for diagnostic and therapeutic applications in human disease.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Systems Biology, HPT E73, ETH Zurich, Wolfgang-Pauli-Str 16, 8093 Zurich, Switzerland.

ABSTRACT
The pancreatic beta cell is responsible for maintaining normoglycaemia by secreting an appropriate amount of insulin according to blood glucose levels. The accurate sensing of the beta cell extracellular environment is therefore crucial to this endocrine function and is transmitted via its cell surface proteome. Various surface proteins that mediate or affect beta cell endocrine function have been identified, including growth factor and cytokine receptors, transporters, ion channels and proteases, attributing important roles to surface proteins in the adaptive behaviour of beta cells in response to acute and chronic environmental changes. However, the largely unknown composition of the beta cell surface proteome is likely to harbour yet more information about these mechanisms and provide novel points of therapeutic intervention and diagnostic tools. This article will provide an overview of the functional complexity of the beta cell surface proteome and selected surface proteins, outline the mechanisms by which their activity may be modulated, discuss the methods and challenges of comprehensively mapping and studying the beta cell surface proteome, and address the potential of this interesting subproteome for diagnostic and therapeutic applications in human disease.

Show MeSH
Related in: MedlinePlus