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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 the Ras/ERK pathway and SST effects through PTPs, SHP-1 and SHP-2. Yellow lines show activation, red lines show inhibition of the corresponding protein. Note SHP-1 and SHP-2 inhibition of growth factor receptors, SHP-1 inhibition of ERK 1/2, SHP-2 inhibition of Raf kinase shown in blue lines. Src and SHP-2 activates SHP-1. As a result, SHP-1 and SHP-2 lead the cells to accumulate in G1 phase and inhibit entry in the S phase of the cell cycle. For simplicity the SSTR subtype-specific effects has not been shown separately. Abbreviations: ATF1, activating transcription factor; CcnD1, cyclin D1; CREB, cAMP responsive element binding protein; ERK, extracellular signal-regulated protein kinase; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; GRB2, growth factor receptor binding protein 2; KSR, kinase suppressor of Ras; mTOR, mammalian Target of Rapamycin; MEK, mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase; MSK, mitogen and stress activated kinase; NF-κB, nuclear factor-κB; p90RSK, p90 ribosomal S6 kinase; RTK, receptor tyrosine kinase; Src, cytosolic tyrosine kinase; SHP-1, SH-2 domain containing cytosolic tyrosine phosphatase 1; SHP-2, SH-2 domain containing cytosolic tyrosine phosphatase 2; SOS, mammalian son-of-sevenless; SST, somatostatin; SSTR, somatostatin receptor.
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fig01: A simplified diagram of the Ras/ERK pathway and SST effects through PTPs, SHP-1 and SHP-2. Yellow lines show activation, red lines show inhibition of the corresponding protein. Note SHP-1 and SHP-2 inhibition of growth factor receptors, SHP-1 inhibition of ERK 1/2, SHP-2 inhibition of Raf kinase shown in blue lines. Src and SHP-2 activates SHP-1. As a result, SHP-1 and SHP-2 lead the cells to accumulate in G1 phase and inhibit entry in the S phase of the cell cycle. For simplicity the SSTR subtype-specific effects has not been shown separately. Abbreviations: ATF1, activating transcription factor; CcnD1, cyclin D1; CREB, cAMP responsive element binding protein; ERK, extracellular signal-regulated protein kinase; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; GRB2, growth factor receptor binding protein 2; KSR, kinase suppressor of Ras; mTOR, mammalian Target of Rapamycin; MEK, mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase; MSK, mitogen and stress activated kinase; NF-κB, nuclear factor-κB; p90RSK, p90 ribosomal S6 kinase; RTK, receptor tyrosine kinase; Src, cytosolic tyrosine kinase; SHP-1, SH-2 domain containing cytosolic tyrosine phosphatase 1; SHP-2, SH-2 domain containing cytosolic tyrosine phosphatase 2; SOS, mammalian son-of-sevenless; 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 the Ras/ERK pathway and SST effects through PTPs, SHP-1 and SHP-2. Yellow lines show activation, red lines show inhibition of the corresponding protein. Note SHP-1 and SHP-2 inhibition of growth factor receptors, SHP-1 inhibition of ERK 1/2, SHP-2 inhibition of Raf kinase shown in blue lines. Src and SHP-2 activates SHP-1. As a result, SHP-1 and SHP-2 lead the cells to accumulate in G1 phase and inhibit entry in the S phase of the cell cycle. For simplicity the SSTR subtype-specific effects has not been shown separately. Abbreviations: ATF1, activating transcription factor; CcnD1, cyclin D1; CREB, cAMP responsive element binding protein; ERK, extracellular signal-regulated protein kinase; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; GRB2, growth factor receptor binding protein 2; KSR, kinase suppressor of Ras; mTOR, mammalian Target of Rapamycin; MEK, mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase; MSK, mitogen and stress activated kinase; NF-κB, nuclear factor-κB; p90RSK, p90 ribosomal S6 kinase; RTK, receptor tyrosine kinase; Src, cytosolic tyrosine kinase; SHP-1, SH-2 domain containing cytosolic tyrosine phosphatase 1; SHP-2, SH-2 domain containing cytosolic tyrosine phosphatase 2; SOS, mammalian son-of-sevenless; SST, somatostatin; SSTR, somatostatin receptor.
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fig01: A simplified diagram of the Ras/ERK pathway and SST effects through PTPs, SHP-1 and SHP-2. Yellow lines show activation, red lines show inhibition of the corresponding protein. Note SHP-1 and SHP-2 inhibition of growth factor receptors, SHP-1 inhibition of ERK 1/2, SHP-2 inhibition of Raf kinase shown in blue lines. Src and SHP-2 activates SHP-1. As a result, SHP-1 and SHP-2 lead the cells to accumulate in G1 phase and inhibit entry in the S phase of the cell cycle. For simplicity the SSTR subtype-specific effects has not been shown separately. Abbreviations: ATF1, activating transcription factor; CcnD1, cyclin D1; CREB, cAMP responsive element binding protein; ERK, extracellular signal-regulated protein kinase; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; GRB2, growth factor receptor binding protein 2; KSR, kinase suppressor of Ras; mTOR, mammalian Target of Rapamycin; MEK, mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase; MSK, mitogen and stress activated kinase; NF-κB, nuclear factor-κB; p90RSK, p90 ribosomal S6 kinase; RTK, receptor tyrosine kinase; Src, cytosolic tyrosine kinase; SHP-1, SH-2 domain containing cytosolic tyrosine phosphatase 1; SHP-2, SH-2 domain containing cytosolic tyrosine phosphatase 2; SOS, mammalian son-of-sevenless; 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