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12.14a: Regulation of the Cell Cycle by Protein Kinases

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  • Signaling Kinases

    Lastly, we will 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. In almost all cases, 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.

    The Kinome

    Name

    Description

    AGC Contain PKA, PKG, and PKC families
    CAMK Ca2+/CAM-dependent PK
    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

    In this chapter we will review the activation by extracellular signals of the kinases in red in the table above. These kinases phosphorylate other proteins within the cell and through associated conformational and charge changes, the phosphorylated proteins are either activated or inhibited in the expression of biological activity.

    Figure: five major protein kinases

    Sig Trans

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    Protein Kinase A (PKA)

    Cascade of events: A transmembrane receptor WITHOUT ENZYMATIC ACTIVITY binds an extracellular chemical signal, causing a conformational change in the receptor which propagates through the membrane. The intracellular domain of the receptor is bound to an intracellular heterotrimeric G protein (since it binds GDP/GTP) in the cell. The G protein dissociates and one subunit interacts with and activates an enzyme - adenylate cyclase- which converts ATP into a second messenger - cyclic AMP (cAMP) - in the cell. cAMP activates protein kinase A (PKA) which phosphorylates proteins at specific Ser or Thr side chains.

    Figure: cyclic AMP

    Receptors which work through an intermediary G protein usually are single polypeptide chains that span the membrane seven times in a serpentine fashion.

    Figure: G PROTEINS AND ADENYLATE CYLASE ACTIVATION

    Updated Gs-alpha/adenylate cyclase complex Jmol14 (Java) | JSMol (HTML5)

    Some signals that activate adenylate cyclase and use cAMP as a second messenger include: corticotrophn, dopamine, epinephrine (β-adrenergic), follicle-stimulating hormone, glucagon, many odorants, prostaglandins E1and E2, and many tastants.

    Some enzymes regulated by cAMP-dependent phosphorylation by PKA

    Enzyme Pathway
    Glycogen Synthase glycogen synthesis
    Phosphorylase Kinase glycogen breakdown
    Pyruvate Kinase Glycolysis
    Pyruvate Dehydrogensae Pyruvate to acetyl-CoA
    Hormone-sensitive Lipase Triacylglyeride breakdown
    Tyrosine Hydroxylase Synthesis of DOPA, dopamine, norepinephrine
    Histone H1 Nucleosome formation with DNA
    Histone H2B Nucleosome formation with DNA
    Protein phosphatase 1 Inhibitor 1 Regulation of protein dephosphorylation
    CREB cAMP regulation of gene expression
    PKA cosensus sequence XR(R/K)X(S/T)B (B = hydrophobic amino acid)

    An example of how epinephrine (a flight/fight hormone) can lead to breakdown of glycogen (your main carbohydrate reserves in muscle and liver) is shown below. A cascade of events, starting with the binding of the hormone to its receptor, followed by activation of adenylate cyclase, which forms cAMP, which activates PKA, which leads to the activation of the enzyme that breaks down glycogen (glycogen phosphorylase) is shown. (For simplicity, G protein involvement is not shown.)

    Figure: Activation of glycogen phosphorylase through activation of PKA.

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    Protein Kinase C (PKC) and calmodulin-dependent kinase (CAM-PK)

    Cascade of Events: A transmembrane receptor WITHOUT ENZYME ACTIVITY binds an extracellular chemical signal, causing a conformational change in the receptor which propagates through the membrane. The intracellular domain of the receptor then binds to an intracellular heterotrimer G protein (since it binds GDP/GTP) in the cell. The G protein dissociates and one subunit interacts with and activates an enzyme - phospholipase C - which cleaves the phospho-head group from a membrane phospholipid - phosphatidyl inositol - 4,5-bisphosphate (PIP2) into two second messengers - diacylglyerol and inositol trisphosphate (IP3). Diacylglycerol binds to and activates protein kinase C (PKC). The IP3 binds to ligand-gated receptor/Ca++ channels on internal membranes, leading to an influx of calcium ions into the cytoplasm. Calcium ions bind to a calcium modulatory protein, calmodulin, which binds to and activates the calmodulin-dependent kinase (CAM-PK). The released calcium ions also activate PKC. As in the previous example, these receptors which interact with G proteins are single polypeptide chains which contain 7 membrane spanning alpha helices. The cycle of degradation and resynthesis of PIP2 is called the PI cycle.

    Figure: PI cycle

    Some signals that activate phospholipase C and make IP3 and diacylglycerol include: acetylcholine (a different class than the type located at the neuromuscular junction that we discussed in the last chapter section), angiotensin II, glutamate, histamine, oxytocin, platelet-derived growth factor, vasopressin, gonadotropin-releasing hormone, and thyrotropin-releasing hormone. Some proteins phosphorylated by PKC include:

    Add table.

    Some kinases regulated by calcium and calmodulin include: myosin light chain kinase, PI-3 kinase, CAM-dependent kinases. Ca/CAM also regulates other proteins which include: adenylate cyclase (brain), Ca-dependent Na channel, cAMP phosphodiesterase, calcineurin (phosphoprotein phosphatase 2B), cAMP gated olfactory channels, NO synthase, and plasma membrane Ca/ATPase.

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