Activation of extracellular-regulated kinase pathways in ovarian granulosacells by the novel growth factor type 1 follicle-stimulating hormone receptor - Role in hormone signaling and cell proliferation

Follicle-stimulating hormone (FSH) regulated growth and function of the ova rian follicle was previously thought to be mediated solely through activati on of G(s)-coupled receptors, In this study, we show for the first time tha t this function is predominantly mediated through the alternatively spliced and novel growth factor type 1 receptor (oFSH-R3) that is also present in the ovary. Immortalized granulosa cells lacking endogenous FSH receptors, w hen transfected with either oFSH-R3 cDNA (JC-RS) or the G(s)-coupled oFSH-R 1 (JC-R1), expressed the corresponding glycosylated receptor. In JC-R3 or J C-R1 cells labeled with bromodeoxyuridine or [H-3]thymidine, FSH: stimulate d the cells to progress through S-phase and divide. The growth promoting ef fect of recombinant FSH in JC-R3 cells was preceded by the rapid activation of ERK1 and ERK2. This effect was hormone-specific and transient. In JC-R3 cells inhibitors like calphostin C, PD98059, Ag 18, or calcium chelators E GTA or 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/AM inhibite d both mitogen-activated protein kinase activation and bromodeoxyuridine in corporation, FSH induced phosphorylation of the FSH-R3 receptor was blocked by pretreating cells with calphostin C, There was no cAMP induction by FSH in JC-R3 cells. The cAMP independent growth promoting effect of FSH is med iated by activation of Ca2+ and mitogen-activated protein kinase-dependent pathways. Thus, alternative splicing of a G-protein coupled receptor create s the expression of a novel receptor motif that can mediate a widely recogn ized function of the glycoprotein hormone.