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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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Selected beta cell surface proteins implicated in important functional aspects of the beta cell. Binding of insulin to the insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R), as well as EGFR signalling, activates downstream effector molecules that positively regulate beta cell function and proliferation. In insulin granule exocytosis glucose is transported across the beta cell membrane via the glucose transporters GLUT2 and GLUT1 in humans. The metabolism of glucose results in a rise in the ATP/ADP ratio, which promotes ATP-sensitive potassium channel (KATP channel) closure, membrane depolarization, and opening of voltage-gated calcium channels. The increasing intracellular Ca2+ concentrations trigger the exocytosis of insulin granules. Insulin secretion is also influenced by fatty acids through G-protein coupled receptor (GPR40) signalling by the mobilisation of endoplasmic reticulum (ER) calcium stores and signalling through protein kinase C (PKC). GLP-1 receptor stimulates glucose induced insulin secretion by increasing cyclic adenosine 3′,5′-monophosphate (cAMP) levels and activation of protein kinase A (PKA) and guanine nucleotide exchange factor EPAC2. PKA and PKC can lead to phosphorylation of multiple proteins involved in the regulation of insulin secretion. In contrast, alpha adrenergic receptors inactivate adenyl cyclase (AC) and the formation of ATP, thus inhibiting insulin release. The solid lines indicate direct, immediate reactions. Note: The figure does not contain details of all the downstream signalling pathways of the depicted beta cell surface proteins. For further explanations, see text. DAG, diacylglycerol; IL-1R, interleukin-1 receptor; IRS, insulin receptor substrate; IP3, inositol 1,4,5-trisphosphate; MEK/ERK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; MHC, major histocompatibility complex; PIP2, phosphatidylinositol 4,5-bisphosphate; PI3K, phosphatidylinositol 3-kinase; PLC, phospholipase C
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Fig2: Selected beta cell surface proteins implicated in important functional aspects of the beta cell. Binding of insulin to the insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R), as well as EGFR signalling, activates downstream effector molecules that positively regulate beta cell function and proliferation. In insulin granule exocytosis glucose is transported across the beta cell membrane via the glucose transporters GLUT2 and GLUT1 in humans. The metabolism of glucose results in a rise in the ATP/ADP ratio, which promotes ATP-sensitive potassium channel (KATP channel) closure, membrane depolarization, and opening of voltage-gated calcium channels. The increasing intracellular Ca2+ concentrations trigger the exocytosis of insulin granules. Insulin secretion is also influenced by fatty acids through G-protein coupled receptor (GPR40) signalling by the mobilisation of endoplasmic reticulum (ER) calcium stores and signalling through protein kinase C (PKC). GLP-1 receptor stimulates glucose induced insulin secretion by increasing cyclic adenosine 3′,5′-monophosphate (cAMP) levels and activation of protein kinase A (PKA) and guanine nucleotide exchange factor EPAC2. PKA and PKC can lead to phosphorylation of multiple proteins involved in the regulation of insulin secretion. In contrast, alpha adrenergic receptors inactivate adenyl cyclase (AC) and the formation of ATP, thus inhibiting insulin release. The solid lines indicate direct, immediate reactions. Note: The figure does not contain details of all the downstream signalling pathways of the depicted beta cell surface proteins. For further explanations, see text. DAG, diacylglycerol; IL-1R, interleukin-1 receptor; IRS, insulin receptor substrate; IP3, inositol 1,4,5-trisphosphate; MEK/ERK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; MHC, major histocompatibility complex; PIP2, phosphatidylinositol 4,5-bisphosphate; PI3K, phosphatidylinositol 3-kinase; PLC, phospholipase C

Mentions: The so far functionally studied surface proteome of pancreatic beta cells is composed of a structurally diverse network of proteins that interacts with environmental molecules, including metabolites, ions, hormones, various peptides and proteins (Fig. 2). According to Gene Ontology (GO) analysis the majority of its members fall into the categories of proteins with receptor, transporter, calcium ion binding, peptidase, kinase, G-protein coupled receptor and ion channel activity [10]. Most of them have also been linked to one of the three most important aspects in the life of a healthy beta cell, namely differentiation, survival/proliferation and insulin secretion. The function of some ‘classical’ beta cell surface receptors and their downstream signalling pathways, depicted in Fig. 2, have been extensively covered elsewhere [20–22], but in the context of mapping the beta cell surface proteome, special attention should also be paid to the proteins mediating cell–cell contacts: when working with primary islets and isolated beta cells their activity will have to be interrupted in most cases, and yet they are pivotal for beta cell function.Fig. 2


The pancreatic beta cell surface proteome.

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

Selected beta cell surface proteins implicated in important functional aspects of the beta cell. Binding of insulin to the insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R), as well as EGFR signalling, activates downstream effector molecules that positively regulate beta cell function and proliferation. In insulin granule exocytosis glucose is transported across the beta cell membrane via the glucose transporters GLUT2 and GLUT1 in humans. The metabolism of glucose results in a rise in the ATP/ADP ratio, which promotes ATP-sensitive potassium channel (KATP channel) closure, membrane depolarization, and opening of voltage-gated calcium channels. The increasing intracellular Ca2+ concentrations trigger the exocytosis of insulin granules. Insulin secretion is also influenced by fatty acids through G-protein coupled receptor (GPR40) signalling by the mobilisation of endoplasmic reticulum (ER) calcium stores and signalling through protein kinase C (PKC). GLP-1 receptor stimulates glucose induced insulin secretion by increasing cyclic adenosine 3′,5′-monophosphate (cAMP) levels and activation of protein kinase A (PKA) and guanine nucleotide exchange factor EPAC2. PKA and PKC can lead to phosphorylation of multiple proteins involved in the regulation of insulin secretion. In contrast, alpha adrenergic receptors inactivate adenyl cyclase (AC) and the formation of ATP, thus inhibiting insulin release. The solid lines indicate direct, immediate reactions. Note: The figure does not contain details of all the downstream signalling pathways of the depicted beta cell surface proteins. For further explanations, see text. DAG, diacylglycerol; IL-1R, interleukin-1 receptor; IRS, insulin receptor substrate; IP3, inositol 1,4,5-trisphosphate; MEK/ERK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; MHC, major histocompatibility complex; PIP2, phosphatidylinositol 4,5-bisphosphate; PI3K, phosphatidylinositol 3-kinase; PLC, phospholipase C
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Fig2: Selected beta cell surface proteins implicated in important functional aspects of the beta cell. Binding of insulin to the insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R), as well as EGFR signalling, activates downstream effector molecules that positively regulate beta cell function and proliferation. In insulin granule exocytosis glucose is transported across the beta cell membrane via the glucose transporters GLUT2 and GLUT1 in humans. The metabolism of glucose results in a rise in the ATP/ADP ratio, which promotes ATP-sensitive potassium channel (KATP channel) closure, membrane depolarization, and opening of voltage-gated calcium channels. The increasing intracellular Ca2+ concentrations trigger the exocytosis of insulin granules. Insulin secretion is also influenced by fatty acids through G-protein coupled receptor (GPR40) signalling by the mobilisation of endoplasmic reticulum (ER) calcium stores and signalling through protein kinase C (PKC). GLP-1 receptor stimulates glucose induced insulin secretion by increasing cyclic adenosine 3′,5′-monophosphate (cAMP) levels and activation of protein kinase A (PKA) and guanine nucleotide exchange factor EPAC2. PKA and PKC can lead to phosphorylation of multiple proteins involved in the regulation of insulin secretion. In contrast, alpha adrenergic receptors inactivate adenyl cyclase (AC) and the formation of ATP, thus inhibiting insulin release. The solid lines indicate direct, immediate reactions. Note: The figure does not contain details of all the downstream signalling pathways of the depicted beta cell surface proteins. For further explanations, see text. DAG, diacylglycerol; IL-1R, interleukin-1 receptor; IRS, insulin receptor substrate; IP3, inositol 1,4,5-trisphosphate; MEK/ERK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; MHC, major histocompatibility complex; PIP2, phosphatidylinositol 4,5-bisphosphate; PI3K, phosphatidylinositol 3-kinase; PLC, phospholipase C
Mentions: The so far functionally studied surface proteome of pancreatic beta cells is composed of a structurally diverse network of proteins that interacts with environmental molecules, including metabolites, ions, hormones, various peptides and proteins (Fig. 2). According to Gene Ontology (GO) analysis the majority of its members fall into the categories of proteins with receptor, transporter, calcium ion binding, peptidase, kinase, G-protein coupled receptor and ion channel activity [10]. Most of them have also been linked to one of the three most important aspects in the life of a healthy beta cell, namely differentiation, survival/proliferation and insulin secretion. The function of some ‘classical’ beta cell surface receptors and their downstream signalling pathways, depicted in Fig. 2, have been extensively covered elsewhere [20–22], but in the context of mapping the beta cell surface proteome, special attention should also be paid to the proteins mediating cell–cell contacts: when working with primary islets and isolated beta cells their activity will have to be interrupted in most cases, and yet they are pivotal for beta cell function.Fig. 2

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