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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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Chart of cell surface proteins predicted to be expressed in human beta cells. At 15–20 %, the predicted human surface membrane proteome constitutes a large part of the whole proteome [7, 8, 100]. Predicted cell surface proteins (blue) [7], anticipated cell surface proteins as determined by mRNA expression in human beta cells by the Beta Cell Gene Atlas (green) [9] and high-confidence human beta cell surface proteins as determined by N-linked glycoprotein cell surface proteomics (red) [10]. Note that for a large proportion of the predicted cell surface proteins no gene expression data are available. The secretome and sheddome were not considered in this graph because of a lack of comprehensive proteomic data
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Fig1: Chart of cell surface proteins predicted to be expressed in human beta cells. At 15–20 %, the predicted human surface membrane proteome constitutes a large part of the whole proteome [7, 8, 100]. Predicted cell surface proteins (blue) [7], anticipated cell surface proteins as determined by mRNA expression in human beta cells by the Beta Cell Gene Atlas (green) [9] and high-confidence human beta cell surface proteins as determined by N-linked glycoprotein cell surface proteomics (red) [10]. Note that for a large proportion of the predicted cell surface proteins no gene expression data are available. The secretome and sheddome were not considered in this graph because of a lack of comprehensive proteomic data

Mentions: The total number and relative abundance of beta cell surface proteins is currently unknown, but computational prediction tools combined with transcriptomic and proteomic approaches can tell us what the beta cell surface may look like (Fig. 1). In a recent bioinformatics approach, a total of 3,702 transmembrane proteins were predicted, accounting for ∼15–20% of all human genes [7] (similar percentages are anticipated for the human secretome [8]). Searching for these proteins in the Beta Cell Gene Atlas [9]—a collection of publically available microarray data generated from the analysis of pancreatic beta cells and related cell types—reveals that, of these, 1,212 genes are expressed in primary human beta cells, while 353 are not (no data are available for the remainder; see Electronic supplementary material [ESM] Table 1). A recent proteomic study aimed at the identification of N-linked glycoproteins identified nearly 1,000 glycoproteins of mouse beta cells and human islets (available online via the dBETA database, http://biodata.ethz.ch/cgi-bin/beta.py), of which 349 proteins were found at the cell surface in the murine beta cell line MIN6 [10]. Of these, 172 proteins are also found in human islets, thus representing potential human beta cell surface proteins [10]. With further progress and refinements in mass spectrometry-based technologies, hypothetical beta cell surface candidate proteins (i.e. bioinformatically predicted surface proteins expressed in beta cells according to transcriptomic data) as well as possibly unanticipated surface proteins (which are, owing to the lack of a signal peptide, not predicted but may localise to the cell surface via unconventional pathways [11]) are likely to be validated or identified. In addition, it is likely that the beta cell surface displays proteins that are also produced in other, non-endocrine tissues, although possibly at different levels. However the beta cell plasma membrane proteome may be defined by beta cell-enriched macromolecules that are shared primarily with other neuroendocrine cell types or that are really beta cell specific. Several studies have indeed identified islet and beta cell enriched surface proteins [12–16]. Hence, comparisons of cell surface proteins between different cell types reveal specificity as well as the selective absence of proteins in beta cells. In fact, the concept of beta cell specific depletion of cell surface proteins has already emerged [17], which can contribute to the understanding of beta cell physiology as well. For example, expression of platelet-derived growth factor receptor declines over the course of a lifetime, which correlates with the age-dependent loss of beta cell proliferative capacity [18]; the lack of monocarboxylate transporter-1 explains the pyruvate paradox (i.e. the failure of pyruvate and lactate to stimulate insulin secretion), which, in turn, avoids inappropriate insulin release during physical exercise [19].Fig. 1


The pancreatic beta cell surface proteome.

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

Chart of cell surface proteins predicted to be expressed in human beta cells. At 15–20 %, the predicted human surface membrane proteome constitutes a large part of the whole proteome [7, 8, 100]. Predicted cell surface proteins (blue) [7], anticipated cell surface proteins as determined by mRNA expression in human beta cells by the Beta Cell Gene Atlas (green) [9] and high-confidence human beta cell surface proteins as determined by N-linked glycoprotein cell surface proteomics (red) [10]. Note that for a large proportion of the predicted cell surface proteins no gene expression data are available. The secretome and sheddome were not considered in this graph because of a lack of comprehensive proteomic data
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3369137&req=5

Fig1: Chart of cell surface proteins predicted to be expressed in human beta cells. At 15–20 %, the predicted human surface membrane proteome constitutes a large part of the whole proteome [7, 8, 100]. Predicted cell surface proteins (blue) [7], anticipated cell surface proteins as determined by mRNA expression in human beta cells by the Beta Cell Gene Atlas (green) [9] and high-confidence human beta cell surface proteins as determined by N-linked glycoprotein cell surface proteomics (red) [10]. Note that for a large proportion of the predicted cell surface proteins no gene expression data are available. The secretome and sheddome were not considered in this graph because of a lack of comprehensive proteomic data
Mentions: The total number and relative abundance of beta cell surface proteins is currently unknown, but computational prediction tools combined with transcriptomic and proteomic approaches can tell us what the beta cell surface may look like (Fig. 1). In a recent bioinformatics approach, a total of 3,702 transmembrane proteins were predicted, accounting for ∼15–20% of all human genes [7] (similar percentages are anticipated for the human secretome [8]). Searching for these proteins in the Beta Cell Gene Atlas [9]—a collection of publically available microarray data generated from the analysis of pancreatic beta cells and related cell types—reveals that, of these, 1,212 genes are expressed in primary human beta cells, while 353 are not (no data are available for the remainder; see Electronic supplementary material [ESM] Table 1). A recent proteomic study aimed at the identification of N-linked glycoproteins identified nearly 1,000 glycoproteins of mouse beta cells and human islets (available online via the dBETA database, http://biodata.ethz.ch/cgi-bin/beta.py), of which 349 proteins were found at the cell surface in the murine beta cell line MIN6 [10]. Of these, 172 proteins are also found in human islets, thus representing potential human beta cell surface proteins [10]. With further progress and refinements in mass spectrometry-based technologies, hypothetical beta cell surface candidate proteins (i.e. bioinformatically predicted surface proteins expressed in beta cells according to transcriptomic data) as well as possibly unanticipated surface proteins (which are, owing to the lack of a signal peptide, not predicted but may localise to the cell surface via unconventional pathways [11]) are likely to be validated or identified. In addition, it is likely that the beta cell surface displays proteins that are also produced in other, non-endocrine tissues, although possibly at different levels. However the beta cell plasma membrane proteome may be defined by beta cell-enriched macromolecules that are shared primarily with other neuroendocrine cell types or that are really beta cell specific. Several studies have indeed identified islet and beta cell enriched surface proteins [12–16]. Hence, comparisons of cell surface proteins between different cell types reveal specificity as well as the selective absence of proteins in beta cells. In fact, the concept of beta cell specific depletion of cell surface proteins has already emerged [17], which can contribute to the understanding of beta cell physiology as well. For example, expression of platelet-derived growth factor receptor declines over the course of a lifetime, which correlates with the age-dependent loss of beta cell proliferative capacity [18]; the lack of monocarboxylate transporter-1 explains the pyruvate paradox (i.e. the failure of pyruvate and lactate to stimulate insulin secretion), which, in turn, avoids inappropriate insulin release during physical exercise [19].Fig. 1

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