Serotonin (5-hydroxytryptamine, 5-HT)1 is one of the best known examples of a neurotransmitter that mediates a wide variety of physiological effects, including peripheral and central actions, through the binding to multiple receptor subtypes (1). The major sites of 5-HT synthesis and storage are located in the periphery, in gut enterochromaffin cells and blood platelets, respectively. The large diversity of 5-HT functions is paralleled by the pharmacological complexity of 5-HT receptors. At least four classes of 5-HT receptors have been distinguished pharmacologically, reflecting the second messenger system to which the receptor is coupled. The family including 5-HT1 and 5-HT5 subtypes of receptors interacts negatively with adenylyl cyclase, the 5-HT2 subfamily of receptors is coupled to the activation of the phospholipase C-, the 5-HT3 receptor is a ligand-gated ion channel, and the family, including 5-HT4, 5-HT6, and 5-HT7 subtypes of receptors, activates adenylyl cyclase (2).5-HT2 receptors mediate many of the central and peripheral physiological functions of 5-HT. Cardiovascular effects include contraction of blood vessels and shape change in platelets; central nervous system effects include neuronal sensitization to tactile stimuli and mediation of hallucinogenic effects of lysergic acid diethylamide and related phenylisopropylamine hallucinogens. The most characterized 5-HT2 receptor subtypes are the 5-HT2A (formerly 5-HT2) and the 5-HT2C (formerly 5-HT1C) both of which stimulate phospholipase C-. Many investigators have observed that some peripheral 5-HT2-like effects of 5-HT are mediated by "atypical" receptors (3). In the mouse, we cloned a new member (5-HT2B) of the 5-HT2 family which is mainly expressed in the cardiovascular system, gut, and developing brain (4). This mouse 5-HT2B receptor shares the highest degree of homology with the other 5-HT2B receptors cloned from the rat fundus (5, 6) and, more recently, from human libraries (7-9) (for review, see Ref. 10) and from Drosophila (11).5-HT, detected early in embryonic development (12), participates in craniofacial (13) and cardiovascular morphogenesis (14, 15) by unknown molecular mechanisms. We have investigated the growth factor properties mediated by the 5-HT2B receptor since (i) both Drosophila 5-HT2 and mouse 5-HT2B receptors are expressed during embryogenesis (11, 16), (ii) the mitogenic activity of 5-HT has been linked mainly to 5-HT2 receptor-dependent stimulation of phospholipase C-/protein kinase C; when expressed at high density in NIH3T3 fibroblasts, both 5-HT2C and 5-HT2A have mitogenic effects induced by 5- HT (17,18). In mammalian cells, the ability to activate the mitogen-activated protein (MAP) kinase cascade is a feature common to many extracellular stimuli, including growth factors, hormones, and neurotransmitters, leading to transcription factor phosphorylation and to cell division (19). The signaling pathways that activate the MAP kinase cascade use receptor tyrosine kinase or non-receptor tyrosine kinases. Other stimuli act...