Signaling Across the Cell Membrane
Let's consider general mechanisms for signal transduction across membranes of any cell that must respond to its environment. Typically the agent that signals a cell to respond is a molecule (or in the case of light sensation a photon) which binds either to a cell surface receptor or to a cytoplasmic receptor if the signaling agent is hydrophobic.
To a first approximation you could consider a cell as a black box with input and resulting output signals. There could be one or more signals, and one or more outputs. The inputs might arrive gradually a reach a threshold before triggering an output or the input might be abrupt leading to an immediate output.
In many cases in eukaryotes, such signaling activates protein kinases in the cell. Kinases are a class of enzymes which use ATP to phosphorylate molecules within the cell.
The names given to kinases shows the substrate which is phosphorylated by the enzyme. For example:
- Hexokinase - an enzyme that uses ATP to phosphorylate hexoses.
- Protein kinase - enzymes that use ATP to phosphorylate proteins within the cell. (Note: Hexokinase is a protein, but is not a protein kinase).
- Phosphorylase Kinase: an enzyme that use ATP to phosphorylate the protein phosphorylase within the cell
If a protein is phosphorylated by a kinase, the phosphate group must eventually be removed by a phosphatase through hydrolysis. If it wasn't, the phosphorylated protein would be in a constant state of either being activated or inhibited. Kinases and phosphatases regulate all aspects of cellular function. Some people estimate that 1-2% of the entire genome may encode kinases and phosphatases. There appears to be about 518 different protein kinases in humans.
Kinases can be classified in many ways. One is substrate specificity: Eukaryotes have different kinases that phosphorylate Ser/Thr or Tyr. Prokaryotes also have His and Asp kinases but these are unrelated structurally to the eukaryotic kinases. There are 11 structurally different families of eukaryotic kinases, which all fold to a similar active site with an activation loop and catalytic loop between which substrates bind. Simple, single cell eukaryotic cells (like yeast) have predominantly cytoplasmic Ser/Thr kinases, while more complex eukaryotic cells (like human) have many Tyr kinases. These include the membrane-receptor Tyr kinases and the cytoplasmic Src kinases.
Manning et al. have analyzed the entire human genome (DNA and transcripts) and have identified 518 different protein kinases, which cluster into 7 main families as shown in the table below. Family membership was determined by sequence comparisons of catalytic domains. They have named the entire repertoire of kinases in the genome the kinome. Alterations in 218 of these appear to be associated with human diseases.
|AGC||Contain PKA, PKG, and PKC families|
|CKI||Casein kinase 1|
|CMGC||Contain CDK, MAPK,GSK3, CLK families|
|STE||homologs of yeast sterile 7, 11, 20 kinases; MAP Kinase|
|PTK||Protein tyrosine kinase|
|PTKL||Protein tyrosine kinase-like|
|RGC||Receptor guanylate kinase|
The figures below .