Cell Signalling
Part of a complex system of communications that governs basic cellular activities & coordinates cell actions
Signal Transduction
any process by which a cell converts one kind of signal/stimuli into another
Types of intracellular signalling
Autocrine, paracrine, endocrine
Autocrine signalling
produced by a cell with a receptor on it
Paracrine signallng
produced by a cell with a neighbouring receptor cell
Endocrine signalling
cell signal that can be transferred to any cell with a receptor
Molecular signalling pathways
Morphogens, notch-delta, RTK’s, transcription factors
Two classes of proteins needed for communication
gap junctions, cell adhesion molecules
Gap Junctions
connexon – transmembrane protein, 4 transmembrane domains, forms a hemichannel, when hemichannels align, material from cell to cell transfers
Cell adhesion molecules
Cadherins & the immunoglobin superfamily – modify structure of cells by adhering material
Morphogens
- Diffusible molecules such as growth factors that specify which cell type will be generated at a specific anatomic site & direct the migration of cells and their processes to their final destination
- Include: retinoic acid, transforming growth factor beta
Retinoic Acid
- Small molecule, diffuses through the plasma membrane and binds to its receptor
- Acts to posteriorize the body
o Anterior/posterior or anteroposterior axis of the embryo is crucial for determining the correct location for limbs & patterning of the nervous system - Insufficient amounts will lead to a more anteriorized structure
Transforming Growth Factor Beta/ BMP
- Members of the TGF-β superfamily include TGF-β, BMPs, activin, and nodal. These molecules contribute to the establishment of dorsoventral patterning, cell fate decisions, and formation of specific organs, including the nervous system, kidneys, skeleton, and blood. We have 3 TGF-B isoforms: TGF-B1, -B2, -B3
Sonic Hedgehog Gene (SHH)
- SHH was the first mammalian ortholog of the drosophila hedgehog gene (Hh) to be identified
- SHH is a secreted morphogen critical to early patterning, cell migration, differentiation
Primary receptor for SHH
Patched (PTCH), a 12-transmembrane domain protein that, in the absence of Shh, inhibits Smoothened (Smo), a seven-transmembrane domain G protein-linked protein, and downstream signaling to the nucleus. If smo is inhibited, a complex with cos2 and fu phosphorylates and cleaves gli to make it a transcriptional repressor
What occurs in the presence of SHH
Ptc inhibition is blocked and downstream events follow, including nuclear translocation of Gli (Gli1, Gli2, Gli3), with transcriptional activation of target genes, such as Ptc-1, Engrailed, and others
- Shh is cleaved, cholersterol added to its N-terminus, making the shh hydrophobic. The modified shh ligand inhibits the receptor, permitting smo signalling which acts on cos2, fu, and sufu which no longer reacts with gli. Activated gli translocates to the nucleus to activate target genes with cAMP binding protein (cBP)
- Sensory and motor neurons are determined by the concentration of morphogens (shh)
WNT/B-Catenin pathway
- Specific WNTS bind to one of the 10 frizzled (FZD) 7-transmembrane cell surface receptors and bind with low-density lipo-protein receptor-related-proteins (LPR5/6) coreceptors, thereby activating downstream intracellular signalling events
What occurs in the absence of WNT
B-catenin is phosphorylated by a multi protein complex and targeted for degradation. Target gene expression is repressed by T-cell factor (TCF)
What occurs in the presence of WNT
WNT binds to FZD receptor, LRP coreceptors, DVL is phosphorylated so it can’t activate GSK-3 and B-catenin is not phosphorylated – accumulates in the cytoplasm, some enters the nucleus to activate target gene transcription
Notch-Delta Pathway
- Notch signalling pathway specifies which cel fate precursor cells will adopt
- Integral for cell fate determination, maintenance of stem cell niches, proliferation, apoptosis and differentiation
- Ligand-receptor binding triggers proteolytic events, some are mediated by secretases, leading to the release of the notch intracellular domain (NICD).
Transcription factors
- Belong to a large class of proteins that regulate the expression of target genes via. activation/repression mechanisms
Receptor tyrosine kinases (RTKs).
- Many growth factors signal by binding to and activating membrane-bound RTKs.
- Essential for the regulation of cellular proliferation, apoptosis, and migration as well as processes such as the growth of new blood vessels and axonal processes in the nervous system
Two types of kinases
Tyrosine and serine-threonine
Vitamin A abnormal function/mutations
The central nervous system (hydrocephalus, spina bifida), eyes (anophthalmia, microphthalmia), face (harelip, cleft palate), dentition, ear (accessory ears, otosclerosis) limb, urinogenital system (cryptorchidism, ectopic ovaries, pseudohermaphrotisism, renal defects), skin (subcutaneous cysts), lungs (hypoplasia), and heart (incomplete ventricular septation, spongy myocardium, aortic arch defects, aorticopulmonary septal defects, valvulus communis)*.
