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Gonadotropin releasing hormone (GnRH) contributes to the maintenance of gonadotrope function by increasing extracellular signal-regulated kinase (ERK) activity subsequent to binding to its cognate G-protein-coupled receptor. As the GnRH receptor exclusively interacts with G q/11 proteins and as receptor expression is regulated in a ␤-arrestin-independent fashion, it represents a good model to systematically dissect underlying signaling pathways. In ␣T3-1 gonadotropes endogenously expressing the GnRH receptor, GnRH challenge resulted in a rapid increase in ERK activity which was attenuated by the epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitor AG1478. In COS-7 cells transiently expressing the human GnRH receptor, agonist-induced ERK activation was independent of free G␤␥ subunits but could be mimicked by shortterm phorbol ester treatment. Most notably, G q/11 -induced ERK activation was sensitive to N17-Ras and to expression of the C-terminal Src kinase but also to other dominant negative mutants of signaling components localized upstream of Ras, like Shc and the EGFR. GnRH as well as phorbol esters led to Ras activation in COS-7 and ␣T3-1 cells, which was dependent on Src and EGFR tyrosine kinases, indicating that both tyrosine kinases act downstream of protein kinase C (PKC) and upstream of Ras. However, Src did not contribute to Shc tyrosine phosphorylation. GnRH or phorbol ester challenge resulted in PKC-dependent EGFR autophosphorylation. Furthermore, a 5-min phorbol ester treatment was sufficient to trigger tyrosine phosphorylation of the platelet-derived growth factor-␤ receptor in L cells. Thus, in several cell systems PKC is able to stimulate Ras via activation of receptor tyrosine kinases. In many cells proliferation and differentiation is regulated by the extracellular signal-regulated kinase (ERK)1 subfamily of MAP kinases. ERKs represent distal members of a threecomponent kinase module through which extracellular stimuli are transmitted into the cell (1). The best studied signaling cascade is initiated by ligand-bound receptor tyrosine kinases (RTKs) which upon autophosphorylation and tyrosine phosphorylation of adaptor proteins like Shc and Grb2 recruit guanine nucleotide exchange factors for the monomeric GTPase Ras. Activated, i.e. GTP-loaded, Ras subsequently engages the ERK-MAPK cascade involving Raf, MAPK/ERK kinase (MEK), and finally ERKs. It has only recently been appreciated that besides classical growth factors like EGF and PDGF, agonists acting at Gprotein-coupled receptors (GPCRs) also play a role in differentiation, proliferation, and even cellular transformation (2, 3). Both pertussis toxin (PTX)-sensitive and -insensitive heterotrimeric G-proteins mediate ERK activation, and distinct signaling pathways are ascribed to GTP-bound ␣ and free ␤␥ Gprotein subunits. In many cells, Ras-dependent ERK activation via GPCRs appears to be mediated by G␤␥ dimers released from PTX-sensitive G-proteins (4). However, G␤␥ subunits derived from PTX-insensitive G␣ q proteins ha...

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Approximately 15-25% of all primary cancers of the lung are classified histologically as small cell lung carcinoma (SCLC), a subtype characterized by rapid growth and a poor prognosis. Neuropeptide hormones like bombesin/gastrin-releasing peptide, bradykinin or galanin are the principal mitogenic stimuli of this tumour entity. The mitogenic signal is transmitted into the cell via heptahelical neuropeptide hormone receptors, which couple to the heterotrimeric G proteins of the G q/11 familiy. Subsequent activation of phospholipase Cb (PLCb) entails the activation of protein kinase C and the elevation of the intracellular calcium concentration. There is mounting evidence to support the notion that calcium mobilization is the key event that initiates different mitogenactivated protein kinase cascades. Neuropeptide-dependent proliferation of SCLC cells relies on parallel activation of the G q/11 /PLCb/Ras/extracellular signal-regulated kinase and the c-jun N-terminal kinase pathways, while selective engagement of either signalling cascade alone results in growth arrest and differentiation or apoptotic cell death. Basic experimental research has the potential to identify and validate novel therapeutic targets located at critical points of convergence of different mitogenic signal transduction pathways. In the case of SCLC, targeting the distinct components of the Ca 2C influx pathway as well as critical Ca 2C -dependent cellular effectors may be rewarding in this regard.