Figure 1. Schematic of the hedgehog-wingless feedback loop that controls parasegment boundary formation in Drosophila embryos. Secreted Hedgehog protein Hh is produced by the Engrailed-expressing En cells in the anterior compartment of each parasegment. Hedgehog protein signals across the future parasegment boundary to the posterior cells of the next parasegment, where it binds to patched receptors (Ptc), which are complexed to another transmembrane molecule, smoothened (Smo). This complex, which also acts to restrict the diffusion of Hedgehog, signals via a transcription factor Ci to activate the expression of wingless (wg) and patched. Wingless protein is secreted and signals, via its own receptor, Drosophila frizzled2 (Frz) and signal transduction pathway, back to the original cell in the adjacent parasegment, where it maintains hedgehog expression. Thus hedgehog not only maintains its own expression via feedback through wingless (i), but also maintains the expression of its receptor, patched (ii), thus ensuring reception and limiting diffusion. (From Shimeld 1999 with permission.)

Figure 2. ‘Receptor conversion model’ of cytokine pleiotropy. In one instance, a cytokine acts on the cells (target cell A) that express a specific receptor. Alternatively, a complex composed of the cytokine and a soluble form of its receptor subunit can act on the cells (target cell B) that express only a receptor subunit and do not respond to the cytokine alone. In this way, the complex acts to provide an alternate target cell on which the original cytokine cannot act and thereby the complex exerts completely different biological actions. (From Hirano 1999 with permission.)

Figure 3. ‘Orchestrating model’ of cytokine pleiotropy, in which distinct cytoplasmic regions of a cytokine or growth factor receptor simultaneously generate contradictory signals. In this particular example, gp130-induced growth signals can be dissected into at least two parts: one is required for G1 to S and S to G2/M cell cycle transitions, and the other required for antiapoptosis. gp130 stimulation induces macrophage differentiation and growth arrest in M1 cells. STAT3 (signal transducers and activators of transcription 3) activation is essential for such events. When STAT3 activation is suppressed, gp130 induces growth-enhancing signals through the tyrosine residue required for mitogen-activated protein kinase (MAPK) activation. gp130-induced neurite outgrowth in PC12 cells is dependent on MAPK activation, while STAT3 activation is inhibitory. Tumor necrosis factor (TNF) induces apoptosis through the activation of the caspase cascade, while it induces antiapoptotic signals through activation of nuclear factor-B (NF-B). Arrow indicates a positive signal; dotted line indicates a negative signal. The resulting chaotic situation could be orchestrated by a conductor to effect a directed biological change according to the balance of the signals, thus bringing order from the chaos. SHP-2: src homology 2-containing tyrosine phosphatase; Grb2: an adaptor protein; Cdc25a: Cell division cycle gene 25A; c-myb: Cellular homologue of retroviral oncogene v-myb; c-myc: Cellular homologue of retroviral oncogene v-myc; FADD: Fas-associated death domain; G1: Gap1 phase of cell cycle; G2/M: Gap2/Mitosis checkpoint of cell cycle; Gab: Grb2-associated protein; gp130: Glycoprotein130; IkB: Inhibitor of NF-kappaB; IKK: Inhibitor KappaB kinase; MAPK: mitogen-activated protein kinase; NIK: NF-kappaB-inducing kinase; p21: (also known as Waf1 and Cip1), a cyclin-dependent protein kinase inhibitory protein; p27: PI-3K: phosphatidylinositol-3 kinase; p19(INK4d): a cyclin-dependent kinase inhibitor; S: Synthesis phase of cell cycle; SOS: Son of sevenless, a Ras/Rac guanine nucleotide exchange factor; TNFR1: Tumor necrosis factor receptor 1; TRADD: TNFR1-associated death domain; TRAF2: TNF receptor-associated factor 2. (From Hirano 1999 with permission.)