Chapter 11: cell signals Without cell signaling, no multicellular organisms could exist. Cells would use their genomes equivalently. Cell signals allow cells to cooperate, signaling each other about how gene expression (use of the DNA) should be regulated: which genes to transcribe, which transcripts to translate, how long proteins should last before destruction, which proteins should be active.

219 /220 human cell types contain identical genomes 219 /220 human cell types contain identical genomes. How is this possible? Simplified summary: Signal transduction mediated Gene expression. Starts before conception. Ends after death.

For example, during embryonic development, a subset of cells express genes coding for proteins needed for muscle form and function. Signal molecules from Other cells in the embryo (shown in red) control this Switch in gene expression. http://www.dmd.nl/images/myod_method_fig1.jpg

Differentiation’s restriction of gene expression allows cells to specialize. Different kinds of cells make different proteins.

Humans have about 220 types of specialized cells that arise from the layers of the folded embryo, a gastrula. The cells carry out different tasks. Zygote –totipotent (all types cells can be formed from it). 1st 10 days: embryonic stem cells (nearly totipotent) By the time the gastrula forms within 10 days, cells are pluripotent and called adult stem cells—committed to one of a few fates.

normal animal development: zygote morula blastulagastruladifferentiated (specialized cells)tissuesorgansorgan systems organism Tissues Organs Organ systems

The difference in whether a cell type chooses one developmental pathway (e.g., brain versus muscle) can be as subtle as how many copies of different transcripts are available. This is particularly true during early development. Bicoid encodes a homeodomain protein that is a transcription factor. Frequent targets (effector proteins) of early control genes are homeodomain proteins like bicoid, determining future responses of the cells.

During development, cells become differentiated if the effector (final step in the signal transduction cascade) for the signal is a transcription factor in the nucleus.

e.g., when signaled by other cells during development, some cells of the mesoderm (middle layer of the gastrula) activate a whole set of genes that result in cells becoming muscle cells.

Complex body structures (like a head or a whole body segment) develop in response to developmental signals if the effector activates a master control gene like a homeotic gene Homeotic genes code transcription factors that recognize a particular set of nucleotides in other genes, binding to them and activating their transcription. Whole sets of genes needed to build a particular body structure can be activated simultaneously by the same signal molecule and its matching receptor protein.

Antenopedia, Noggin, and Trithorax Homeotic gene mutations show how activation of a single master control gene by a cell signal can have a dramatic effect on development. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A2609 ncbi.nlm.nih.gov http://neurophilosophy.wordpress.com/2006/08/09/the-role-of-hox-genes-in-development/

Post-translational modifications allow membrane receptor proteins to convey signals. Via multi-protein signal transduction cascades that end with an effector protein (does the signalled task). Adding phosphate groups changes the 3D shape (tertiary structure) of proteins in the signal pathway. Kinases are protein enzymes that add phosphate groups to another protein. This shape change may switch the protein from inactive to active 3D conformation. Later, a phosphatase (phosphate group removing enzyme) returns each protein to its inactive shape.

Normal development and normal day to day cooperative activity of cells requires that signals be sent in the right cells at the right times and at the correct levels. Diseases like cancer, diabetes, dwarfism occur due to miscommunication of cells.

What changes in gene expression cause cancer, a disease in which cells cycle abnormally? Effectors for growth factor receptor mediated signal pathways activate transcription factors that make proteins needed to stimulate cell division. Cancer often arise due to activating mutations (gain of function) of proteins in the growth factor receptor mediated signal pathway.

You must be able to sketch and label the signalling molecules, plus discuss the importance, of Tyrosine kinase receptor signal pathways G protein linked receptors that activate PKCignal pathways G protein linked receptors that activate PLC signal pathways Steroid receptor signal pathways

Tyrosine kinase receptor pathways

Tyrosine kinases activate downstream kinases, then return to inactive states when dephosphorylated by a phosphatase. They can be reused.

G protein linked receptor proteins utilize non-protein “second messengers” and fall into 2 main categories: PLC stimulating and PKC stimulating PLC stimulating: ultimate response is to release Ca ions from intracellular stores so that proteins activated by Ca++ binding are activated) –example: during muscle contraction, acetylcholine receptors link to a G protein, then to PLC that makes lipids (DAG, etc) that cause Ca release from special ER called sarcoplasmic reticulum. This allows muscle contraction. http://www.youtube.com/watch?v=WRxsOMenNQM

G protein linked receptor proteins utilize non-protein “second messengers” and fall into 2 main categories: PLC stimulating (ultimate response is to release Ca ions from intracellular stores so that proteins activated by Ca++ binding are activated)

PKC stimulating Signal receptor G protein phosphorylated G protein (active) activate adenyl cyclase make second messenger cAMP activate protein kinase A (PKA) activate effectors http://www.youtube.com/watch?v=DGkh7SGacgk e.g. many neurotransmitters work this way