Signaling Systems in Development

Sonic HedgeHog

• FUNCTION: binds to the patched (ptc) receptor, which functions in association with smoothened (smo), to activate the transcription of target genes. in the absence of shh, ptc represses the constitutive signaling activity of smo . also regulates another target, the gli oncogene. Intercellular signal essential for a variety of patterning events during development: signal produced by the notochord that induces ventral cell fate in the neural tube and somites, and the polarizing signal for patterning of the anterior-posterior axis of the developing limb bud. displays both floor plate-and motor neuron-inducing activity.
• SUBCELLULAR LOCATION: the c-terminal peptide diffuses from the cell, while the n-terminal peptide remains associated with the cell surface. is also secreted in either cleaved or uncleaved form to mediate signaling to other cells 

Patched - SHH Receptor

• FUNCTION: acts as a receptor for sonic hedgehog (shh), indian hedgehog (ihh) and desert hedgehog (dhh). Associates with the smoothened protein (smo) to transduce the hedgehog's proteins signal. Seems to have a tumor suppressor function, as inactivation of this protein is probably a necessary, if not sufficient step for tumorigenesis.
• DEVELOPMENTAL STAGE: in the embryo, found in all major target tissues of sonic hedgehog, such as the ventral neural tube, somites, and tissues surrounding the zone of polarizing activity of the limb bud.

Smoothened (co-receptor)

• FUNCTION: g protein-coupled receptor that probably associates with the patched protein (ptch) to transduce the hedgehog's proteins signal. binding of sonic hedgehog (shh) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (smo).
• SUBCELLULAR LOCATION: integral membrane protein. belongs to family fz/smo of g-protein coupled receptors.

(A) In the absence of Hedgehog, the Patched receptor inhibits Smoothened probably by promoting the degradation or intracellular sequestration of Smoothened. The Ci protein is located in a protein complex and is cleaved to form a transcriptional repressor, which accumulates in the nucleus to help keep Hedgehog target genes inactive. The protein complex includes the serine/threonine kinase Fused, the anchoring protein Costal (which binds the complex to microtubules), and the adaptor protein Suppressor of Fused. (B) Hedgehog binding to Patched relieves the inhibition of Smoothened, which now signals to the protein complex to stop processing Ci, to dissociate from microtubules, and to release the unprocessed Ci so it can accumulate in the nucleus and activate the transcription of Hedgehog-responsive genes. Most of the molecular events in the pathway are unknown.

Wnt proteins

• DEFINITION A  family of highly conserved secreted signaling molecules that regulate cell-to-cell interactions during embryogenesis. Wnt (wingless) genes and Wnt signaling are also implicated in cancer. Insights into the mechanisms of Wnt action have emerged from several systems: genetics in Drosophila and Caenorhabditis elegans; biochemistry in cell culture and ectopic gene expression in Xenopus embryos. Many Wnt genes in the mouse have been mutated, leading to very specific developmental defects.
• RECEPTOR - FRIZZLED As currently understood, Wnt proteins bind to receptors of the Frizzled family on the cell surface. Through several cytoplasmic relay components, the signal is transduced to beta-catenin, which then enters the nucleus and forms a complex with TCF to activate transcription of Wnt target genes. . Wnt signaling has been discussed in and excellent web page maintained by Roel Nusse
• CO-RECEPTOR  protein is related to the low density lipoprotein (LDL) receptor protein and is therefore called LDL-receptor-related protein (LRP). It is uncertain how Frizzled and LRP activate Dishevelled, which relays the signal onward.
• ACTION (below) (A) In the absence of a Wnt signal, some b-catenin is bound to the cytosolic tail of cadherin proteins (not shown) and any cytosolic b-catenin becomes bound by the APC-axin-GSK-3b degradation complex. In this complex, b-catenin is phosphorylated by GSK-3b, triggering its ubiquitylation and degradation in proteasomes.Wnt -responsive genes are kept inactive by the Groucho corepressor protein bound to the gene regulatory protein LEF-1/TCF. (B) Wnt binding to Frizzled and LRP activates Dishevelled by an unknown mechanism. By an equally mysterious mechanism, which requires casein kinase 1 (not shown), this leads to the inactivation of GSK-b3 in the degradation complex. As a result, the phosphorylation and degradation of b-catenin is inhibited, and b-catenin accumulates in the cytoplasm and nucleus. In the nucleus, b-catenin binds to LEF-1/TCF, displaces Groucho, and acts as a coactivator to stimulate the transcription of Wnt target genes.

Wnt and Hedgehog signaling Compared

From Nusse Development 130, 5297-5305 2003 The Company of Biologists Ltd

Fibroblast Growth Factor

Fibroblast Growth Factor (FGF) was originally identified as acidic or basic, and we now know there to be at least 17 different FGFs. These protein growth factors are bound by 4 different cell membrane receptors (FGFR1-4). FGFRs belong to the tyrosine kinase receptor family.

• FUNCTION: the heparin-binding growth factors are angiogenic agents in vivo and are potent mitogens for a variety of cell types in vitro. there are differences in the tissue distribution and concentration of these 2 growth factors.

FGF Receptor

• FUNCTION: receptor for basic fibroblast growth factor.
• CATALYTIC ACTIVITY: ATP + protein tyrosine = ADP + protein tyrosine phosphate.

Platelet derived Growth Factor (PDGF) Receptor Compared with FGF receptor