Activation of Nuclear Factor κB by Somatostatin Type 2 Receptor in Pancreatic Acinar AR42J Cells Involves Gα14 and Multiple Signaling Components

Abstract

Somatostatin is an endogenous regulatory peptide secreted by a wide range of tissues including neuroendocrine, inflammatory, and immune cells to inhibit the release of various hormones and growth hormones. These inhibitory actions are mediated through heptahelical transmembrane G protein-coupled receptors (GPCRs).2 To date, five distinct subtypes of somatostatin receptors (SSTRs) have been cloned (1). Among the various subtypes, the type 2 somatostatin receptor (SSTR2) has been studied extensively because of its broad clinical applications. Somatostatin analogs targeting SSTR2 have been used as treatments for rheumatoid arthritis, cystitis and other inflammatory diseases (2). Moreover, somatostatin-related compounds hold promise against pancreatic diseases. Abundant SSTR2 expressions are generally detected from cells with pancreatic inflammatory and tumoral diseases (3). In fact, somatostatin administration has been shown to relieve the severities of acute pancreatitis (4), pancreatic adenocarcinoma, and carcinoids (5).As a G i/o -coupled receptor, SSTR2 inhibits adenylyl cyclase and regulates several subsets of K ϩ channels and voltage-dependent Ca 2ϩ channels upon agonist binding. Furthermore, modulation of the activities of tyrosine phosphatase and mitogen-activated protein kinases (MAPKs) by SSTR2 has been well documented (1). Recent studies suggest that SSTR2 can also employ other G proteins such as G 14 and G 16 for signal transduction (6, 7). Its ability to interact functionally with G␣ 14 is particularly interesting. G␣ 14 is a member of the G q family and has more than 80% homology with G␣ q . Upon activation by SSTR2, G␣ 14 stimulates phospholipase C␤ (PLC␤) activity and the production of inositol trisphosphate. Unlike ubiquitously expressed G␣ q/11 proteins, G␣ 14 is expressed predominantly in pancreas, spleen, lung, kidney, testis, bone marrow, several early myeloid and progenitor B cells (8), and many of these tissues also express SSTR2 (1); its mRNA has been detected in normal pancreatic islets (9) as well as tumoral pancreatic acinar cells (10). Signaling via G␣ 14 may provide SSTR2 with the capacity to alter gene expression through the activation of kinases and transcription factors. G 14 -coupled opioid receptors, close relatives of SSTR2, have been shown to activate c-Jun N-terminal kinases (JNKs) (11) and the signal transducer and activator of transcription 3 (STAT3) (12). Although the upstream cellular signals of SSTR2 have been delineated, the mechanism underlying the antiinflammatory and antitumoral effects of somatostatin remains poorly understood. One possible mechanism may involve nuclear factor-B (NFB), a ubiquitous heterodimeric transcription factor that regulates inflammation and cell survival and differentiation (13). In the inactive state, NFB is anchored to inhibitor B␣ (IB␣) in the cytosol. Upon activation, a key regulatory complex, IB kinase (IKK), comprising two catalytic subunits (IKK␣ and IKK␤) and a linker (IKK␥/NEMO) is stimulated by phosphoryla-* This work was supported in ...

Rainbow trout somatostatin receptor subtypes SSTR1A, SSTR1B, and SSTR2 differentially activate the extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling pathways in transfected cells

“…For example, SSTR1 mediated the activation of the ERK pathway in human SH-SY5Y cells and in BON-1 cells (Stirnweis et al 2002, Ludvigsen et al 2004. In addition, the involvement of the c-Raf-MEK-ERK pathway was critical to SS activation of IKK/NFkB through mammalian SSTR2 in rat AR4-2J cells (Liu & Wong 2005). Similarly, SSTR1 and SSTR2 mediated SS-stimulated PI3K-dependent activation of Akt in human ocular ciliary epithelium and rat Kupffer cells (Valatas et al 2004, Ghosh et al 2006.…”

“…There are multiple points of communication between the PI3K/Akt pathway and the ERK pathway as the latter integrates signals from a host of effector molecules (Liu & Wong 2005). PI3Ks can enhance ERK 1/2 activation through stimulation of G bg subunits that are upstream of ERK (Yart et al 2002).…”

“…Specific linkages between SSTR subtypes and particular effector pathways and biological responses also are known. For example, SSTR1 and SSTR2 in human and rat cell lines link to extracellular signal-regulated kinase (ERK) subfamily of MAPKs and to the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway (Valatas et al 2004, Liu & Wong 2005, Ghosh et al 2006. In addition, mammalian SSTR1 mediates SS inhibition of cell proliferation, whereas SSTR2 appears to mediate SS inhibition of pituitary GH and pancreatic insulin (Florio et al 2000, Sheridan et al 2000.…”

Selective agonism in somatostatin receptor signaling and regulation

“…In addition to activating the Gi/Go family of G proteins, somatostatin receptors can act via pertussis toxin independent mechanisms. In some cases these mechanisms involve activation of pertussis toxin insensitive G proteins, such as G 12 or G 14 (Hou et al, 1994;Komatsuzaki et al, 2001;Lin et al, 1996;Liu and Wong, 2005) whereas in other instances a direct interaction between sst receptors and phosphatases or kinases has been proposed (Bousquet et al, 2006;Ferjoux et al, 2003;Lopez et al, 1996). The list of molecules that bind to activated somatostatin receptors to initiate intracellular signaling is still undoubtedly incomplete and will continue to expand with additional studies.…”

Overexpression of SSTR2 inhibited the growth of SSTR2-positive tumors via multiple signaling pathways

“…However, despite of the contradictory information obtained in different cell types using different SST analogues, it is generally accepted that all five SSTR subtypes are coupled to inhibition of the adenylyl cyclase-cAMP pathway and stimulate phosphotyrosyl protein phosphatase (PTP) [2]. All five subtypes also interfere with the MAPK pathway to modulate cell proliferation, although the precise mechanisms seem to be subtype-and cell typespecific [14,15].…”