Inhibitory role of the somatostatin receptor SST2 on the intracrine-regulated cell proliferation induced by the 210-amino acid fibroblast growth factor-2 isoform: implication of JAK2.
The fibroblast growth factor (FGF)-2 isoform of 210 amino acids (HMW FGF-2) contains a nuclear localization sequence (NLS) and is targeted to the nucleus. This FGF-2 isoform allows cells to grow in low serum concentrations through still unknown mechanisms called intracrine regulations. Different peptide hormones and cytokines have been found to be nuclearized through NLS and to induce cell proliferation. The existence of molecules acting as negative regulators of the intracrine-induced cell growth has not been explored. Pancreatic cells AR4-2J were stably transfected to express selectively the HMW FGF-2. We demonstrated that activation of the somatostatin receptor subtype SST2 by the somatostatin analogue RC-160 in serum-deprived medium inhibits the mitogenic effect of the HMW FGF-2, without affecting growth of control cells. The signaling pathway implicates Galphai/JAK2/SHP-1. The Galphai inhibitor pertussis toxin and the JAK2 inhibitor AG490 abrogate the inhibitory effect of RC-160 on HMW FGF-2-induced cell growth. Co-immunoprecipitation studies demonstrate the constitutive association of JAK2 and SHP-1, and RC-160 induces a rapid activation of both proteins followed by the dissociation of the complex. AG490 prevents the RC-160 induced SHP-1 activation indicating the implication of JAK2 in this process. JAK2 and SHP-1 are immunoprecipitated with SST2 in basal conditions indicating the existence of a functional signaling complex at the receptor level. In summary, these data provide the following evidence: 1) the intracrine-induced proliferation can be reversed by extracellular acting polypeptides; 2) SST2 inhibitory signaling may involve the JAK2/SHP-1 pathway.
Hortala
Marylis
M
INSERM U 531, Institut Louis Bugnard, CHU Rangueil, Toulouse, Cédex 4, France.
Ferjoux
Geraldine
G
Estival
Agnes
A
Bertrand
Claudine
C
Schulz
Stefan
S
Pradayrol
Lucien
L
Susini
Christiane
C
Clemente
Francois
F
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry / Q000235:genetics*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D007536:Isomerism; D053614:Janus Kinase 2; D010190:Pancreatic Neoplasms; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology
D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D017481:Receptors, Somatostatin; D016222:Fibroblast Growth Factor 2; C051458:vapreotide; D013004:Somatostatin; C093733:somatostatin receptor 2; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509250:Ptpn6 protein, rat; D019206:GTP-Binding Protein alpha Subunits, Gi-Go