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Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1--molecular pathways.

Cakir M, Dworakowska D, Grossman A - J. Cell. Mol. Med. (2010)

Bottom Line: Like most endocrine tumours, NETs also express somatostatin (SST) receptors (subtypes 1-5) whose ligand SST is known to inhibit endocrine and exocrine secretions and have anti-tumour effects.SST is a potent anti-proliferative and anti-secretory agent for some NETs.Further studies will focus on critical points of SSTR biology such as homo- and heterodimerization of SSTRs and the differences between post-receptor signalling pathways of SSTR subtypes.

View Article: PubMed Central - PubMed

Affiliation: Selcuk University, Meram School of Medicine, Division of Endocrinology and Metabolism, Konya, Turkey. cakirmehtap@yahoo.com

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A simplified diagram of PI3K/Akt pathway and SST effects through PTP SHP-1. Arrowheads show activation, bold lines with rounded heads show inhibition of the corresponding protein. Note direct inhibition of growth factor receptor and p85 regulatory subunit of PI3K, and indirect inhibition of Akt pathway by SHP-1 shown in dotted lines. As a result, SHP-1 cause up-regulation of p21cip1/waf1 and p27kip1 and the tumour suppressor gene Zac1 and activation of caspase 8 and pro-apoptotic protein Bax. For simplicity, the SSTR subtype-specific effects has not been shown separately. Abbreviations: BAD, BCL2-antagonist of death; CcnD1, cyclin D1; CcnE, cyclin E; ERK, extracellular signal-regulated protein kinases; HDM2, human homolog of murine double minute ubiquitin ligase; GSK-3, glycogen synthase kinase-3; IKK, IκB kinase; mTOR, mammalian target of Rapamycin; NF-κB, nuclear factor-κB; p21, cyclin dependent kinase inhibitor p21Cip1/WAF1; p27, cyclin dependent kinase inhibitor p27Kip1; PDK1, phosphoinositide-dependent kinase 1; RTK, receptor tyrosine kinase; SHP-1, SH-2 domain containing cytosolic tyrosine phosphatase 1; SST, somatostatin; SSTR, somatostatin receptor.
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fig02: A simplified diagram of PI3K/Akt pathway and SST effects through PTP SHP-1. Arrowheads show activation, bold lines with rounded heads show inhibition of the corresponding protein. Note direct inhibition of growth factor receptor and p85 regulatory subunit of PI3K, and indirect inhibition of Akt pathway by SHP-1 shown in dotted lines. As a result, SHP-1 cause up-regulation of p21cip1/waf1 and p27kip1 and the tumour suppressor gene Zac1 and activation of caspase 8 and pro-apoptotic protein Bax. For simplicity, the SSTR subtype-specific effects has not been shown separately. Abbreviations: BAD, BCL2-antagonist of death; CcnD1, cyclin D1; CcnE, cyclin E; ERK, extracellular signal-regulated protein kinases; HDM2, human homolog of murine double minute ubiquitin ligase; GSK-3, glycogen synthase kinase-3; IKK, IκB kinase; mTOR, mammalian target of Rapamycin; NF-κB, nuclear factor-κB; p21, cyclin dependent kinase inhibitor p21Cip1/WAF1; p27, cyclin dependent kinase inhibitor p27Kip1; PDK1, phosphoinositide-dependent kinase 1; RTK, receptor tyrosine kinase; SHP-1, SH-2 domain containing cytosolic tyrosine phosphatase 1; SST, somatostatin; SSTR, somatostatin receptor.

Mentions: The anti-proliferative action of SST-activated PTPs depends on altered growth factor signalling through the selective dephosphorylation and inactivation of their receptors, plus inhibition of one of the most important MAPK pathways for cell proliferation, namely the extracellular signal-regulated protein kinase 1/2 (ERK 1/2) pathway (Fig. 1), and control of the activity of another important downstream signalling pathway, PI3K/Akt (Fig. 2) [101]. The inhibition of the ERK 1/2 pathway can occur either indirectly via the inhibition of the growth factor tyrosine kinase receptors or directly by dephosphorylating ERK 1/2 or by hyperactivation of ERK 1/2 (see below) [102, 103]. Such altered growth factor signalling through the selective dephosphorylation and inactivation of their receptors have been reported for SHP-1 with the insulin receptor, for SHP-2 with the insulin, EGF and platelet-derived growth factor (PDGF) receptor [104–107], for DEP-1 with PDGF and the vascular endothelial growth factor receptor [108, 109] and for PTP1B with the EGF receptor [110].


Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1--molecular pathways.

Cakir M, Dworakowska D, Grossman A - J. Cell. Mol. Med. (2010)

A simplified diagram of PI3K/Akt pathway and SST effects through PTP SHP-1. Arrowheads show activation, bold lines with rounded heads show inhibition of the corresponding protein. Note direct inhibition of growth factor receptor and p85 regulatory subunit of PI3K, and indirect inhibition of Akt pathway by SHP-1 shown in dotted lines. As a result, SHP-1 cause up-regulation of p21cip1/waf1 and p27kip1 and the tumour suppressor gene Zac1 and activation of caspase 8 and pro-apoptotic protein Bax. For simplicity, the SSTR subtype-specific effects has not been shown separately. Abbreviations: BAD, BCL2-antagonist of death; CcnD1, cyclin D1; CcnE, cyclin E; ERK, extracellular signal-regulated protein kinases; HDM2, human homolog of murine double minute ubiquitin ligase; GSK-3, glycogen synthase kinase-3; IKK, IκB kinase; mTOR, mammalian target of Rapamycin; NF-κB, nuclear factor-κB; p21, cyclin dependent kinase inhibitor p21Cip1/WAF1; p27, cyclin dependent kinase inhibitor p27Kip1; PDK1, phosphoinositide-dependent kinase 1; RTK, receptor tyrosine kinase; SHP-1, SH-2 domain containing cytosolic tyrosine phosphatase 1; SST, somatostatin; SSTR, somatostatin receptor.
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Related In: Results  -  Collection

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fig02: A simplified diagram of PI3K/Akt pathway and SST effects through PTP SHP-1. Arrowheads show activation, bold lines with rounded heads show inhibition of the corresponding protein. Note direct inhibition of growth factor receptor and p85 regulatory subunit of PI3K, and indirect inhibition of Akt pathway by SHP-1 shown in dotted lines. As a result, SHP-1 cause up-regulation of p21cip1/waf1 and p27kip1 and the tumour suppressor gene Zac1 and activation of caspase 8 and pro-apoptotic protein Bax. For simplicity, the SSTR subtype-specific effects has not been shown separately. Abbreviations: BAD, BCL2-antagonist of death; CcnD1, cyclin D1; CcnE, cyclin E; ERK, extracellular signal-regulated protein kinases; HDM2, human homolog of murine double minute ubiquitin ligase; GSK-3, glycogen synthase kinase-3; IKK, IκB kinase; mTOR, mammalian target of Rapamycin; NF-κB, nuclear factor-κB; p21, cyclin dependent kinase inhibitor p21Cip1/WAF1; p27, cyclin dependent kinase inhibitor p27Kip1; PDK1, phosphoinositide-dependent kinase 1; RTK, receptor tyrosine kinase; SHP-1, SH-2 domain containing cytosolic tyrosine phosphatase 1; SST, somatostatin; SSTR, somatostatin receptor.
Mentions: The anti-proliferative action of SST-activated PTPs depends on altered growth factor signalling through the selective dephosphorylation and inactivation of their receptors, plus inhibition of one of the most important MAPK pathways for cell proliferation, namely the extracellular signal-regulated protein kinase 1/2 (ERK 1/2) pathway (Fig. 1), and control of the activity of another important downstream signalling pathway, PI3K/Akt (Fig. 2) [101]. The inhibition of the ERK 1/2 pathway can occur either indirectly via the inhibition of the growth factor tyrosine kinase receptors or directly by dephosphorylating ERK 1/2 or by hyperactivation of ERK 1/2 (see below) [102, 103]. Such altered growth factor signalling through the selective dephosphorylation and inactivation of their receptors have been reported for SHP-1 with the insulin receptor, for SHP-2 with the insulin, EGF and platelet-derived growth factor (PDGF) receptor [104–107], for DEP-1 with PDGF and the vascular endothelial growth factor receptor [108, 109] and for PTP1B with the EGF receptor [110].

Bottom Line: Like most endocrine tumours, NETs also express somatostatin (SST) receptors (subtypes 1-5) whose ligand SST is known to inhibit endocrine and exocrine secretions and have anti-tumour effects.SST is a potent anti-proliferative and anti-secretory agent for some NETs.Further studies will focus on critical points of SSTR biology such as homo- and heterodimerization of SSTRs and the differences between post-receptor signalling pathways of SSTR subtypes.

View Article: PubMed Central - PubMed

Affiliation: Selcuk University, Meram School of Medicine, Division of Endocrinology and Metabolism, Konya, Turkey. cakirmehtap@yahoo.com

Show MeSH
Related in: MedlinePlus