ActivationIn Vitroof Somatostatin Receptor Subtypes 2, 3, or 4 Stimulates Protein Tyrosine Phosphatase Activity in Membranes from Transfected Ras-Transformed NIH 3T3 Cells: Coexpression with Catalytically Inactive SHP-2 Blocks Responsiveness

Abstract

Somatostatin receptors (sstr) subtypes 1-5 were transiently expressed in NIH 3T3 cells stably transformed with Ha-Ras(G12V) to assess the ability of each receptor to stimulate protein tyrosine phosphatase (PTPase) activity in vitro. Treatment of membranes from sstr2-, sstr3-, or sstr4-expressing cells with somatostatin-14 plus guanyl-5'-yl imidodiphosphate (GMPPNP) increased PTPase activity, and this stimulation was pertussis toxin-sensitive. Somatostatin alone, GMPPNP alone, or somatostatin plus GDP were ineffective under these conditions. sstr1 and sstr5 failed to increase PTPase activity although both receptors were expressed, as assessed by appearance of high-affinity binding sites for [125I-Tyr11]somatostatin-14. Somatostatin plus GMPPNP stimulated PTPase activity in vitro when sstr2 was coexpressed with wild type PTP1B or a Cys to Ser (C/S), catalytically inactive PTP1B or with wild type SH2-domain containing PTPase SHP-2. However, coexpression with catalytically inactive C/S SHP-2 abrogated this response. Thus, three of the five cloned sstr's can couple to activate PTPase in this cellular background. Abrogation of the response by C/S SHP-2 strongly suggests, but does not prove, a role for SHP-2 in the mechanism.

Biological and Biochemical Basis of the Differential Efficacy of First and Second Generation Somatostatin Receptor Ligands in Neuroendocrine Neoplasms

“…In primary cultures of GH-secreting and non-functioning pituitary adenomas, LAN induces anti-proliferative activity through the induction of a PTP activity [49,50], while OCT triggers SHP1 activity in GH4C1 rat pituitary adenoma cell line [51]. SHP1 and/or SHP2 activities are also induced by SST 1 [52,53], SST 2 [54,55], SST 3 [55], and SST 4 [55,56], while PTPη is activated by SST 1 , SST 2 , and SST 5 , as shown in cells endogenously expressing the different SST subtypes [41]. The molecular mechanisms connecting SSTs and PTPs have not been completely clarified, but likely are not directly induced by G protein activation and involve the modulation of different intracellular transducers [47].…”

Coupling of rat somatostatin receptor subtypes to a G‐protein gated inwardly rectifying potassium channel (GIRK1)

“…The actions of these two agonists are mediated by at least five different somatostatin receptor subtypes (SSTR1–SSTR5), which are all coupled to G‐proteins of the pertussis toxin sensitive G i /G o class. In heterologous expression systems it has been shown that, dependent on the cellular environment, these receptors can be coupled to the inhibition of adenylyl cyclase [2]and voltage‐dependent calcium channels [3], the activation of tyrosine phosphatases [4], phospholipase C [5]and of a phospholipase A 2 [6]. In addition, it has frequently been observed in neuronal and neuroendocrine cells that SST leads to the hyperpolarization of the cell membrane by activation of G‐protein gated inwardly rectifying potassium (GIRK) channels [7].…”

Somatostatin and Somatostatin Receptors in Tumour Biology

“…Activation of Other factors associated with the direct effect of SSTR-induced antiproliferation are protein tyrosine phosphatases (PTPases) [28]. Previous studies using Ras-transformed NIH 3T3 cells have described how the PTPases in these cells are activated by SSTR2, SSTR3 and SSTR4 [29]. Florio et al demonstrated SSTR1-induced cell growth inhibition in transfected CHO-K1 cells by activating SHP-2, which resulted in the MAPK pathway's stimulation [21].…”