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| [image]
Cartoon represents how cells communicate with their surroundings. Green area represents ligands, which interact with the various surface receptors which goes through cascade to ultimately provide a biological response (yellow) |
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| Relatively small proteins released by some cells, make their way through the intercellular space, and impinge on other cells, carrying with them specific biological signals. |
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| Factors that stimulate cell proliferation. Example - PDGF. Platelet derived growth factor is a potent stimulator of fibroblasts, which form the connective tissues beneath epithelia |
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| Kinase Signaling Proteins |
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Definition
Protein kinases operate by removing the high energy gamma phosphate from ATP and attaching it to the hydroxyl groups in the side chains of serine, threonine, or tyrosine residues. Once phosphorylated, the substrate protein may be functionally altered and would therefore alter functions of downstream targets.
Example Src oncogene. Is a phosphoprotein, which means that it carried phosphate groups with it, so it could serve as a substrate for phosphorylation or autophosphorylate. |
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| Actions of Protein Kinases |
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| [image]
This demonstrates that in the presence of Src, the mouse fibroblasts in NIH 3T3 cells are phosphorylated and have noticable bands along the various weight markers. |
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| Inhibitory vs. Stimulatory Phosphorylation |
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| Picture demonstrates how the Phosphorylation of the Atk/PKB kinase can either activate (angiogenesis) or inactivate (apoptosis/proliferation) cell functions.[image] |
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| Once the ligand is bound, kinases present the in cytoplasmic domain of the receptor begin to phosphorylate cytoplasmic proteins, which begin the cascade. |
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| Ligand independent firing |
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Definition
| v-erbB and HER2-onc are examples of mutations that cause constituitive firing of receptors independent of the ligand (GF). HER2-onc has an amino acid subsitution in its transmembrane section, allowing it to fire independently. v-erbB has a drastically altered ectodomain, namely a truncated ligand receptor. |
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| Other causes of ligand independent firing |
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Definition
| The over-expression of ligand receptors can lead to ligand independent firing. |
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| Incomplete (btwn pages 131-141) |
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| TGF beta suppresses epitheilial cell division, and functions as a heterodimer. Upon ligand binding, the type II subunit (which has consituitively active serine/threonin kinase domain) is brought within close proximity of the TGF beta type I subunit, which it phosphorylates. This activates the tpye I receptor which phosphorylates the cytosolic proteins (Smad 2/3, which upon phosphorylation binds to Smad 4, which fits in a transcriptional activator) which cascade, suppressing division. |
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| The Patched/Smoothened (Hedgehog) signaling system |
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Definition
| [image]
Normally, Smoothened, a seven-membrane spanning surface receptor is functionally inert, being inhibited by patched, which contains 12 transmembrane segments. Under these conditions, Gli is cleaved into a protein that moves into the nucleus, where it operates as a repressor of transcription. However, when the Hedgehog ligand binds to Patched, the latter releases its inhibitory grip on Smoothened, which prevents cleavage of Gli so it becomes an inducer. |
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| Defects in the Patched/Smoothened |
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Definition
| Inactivation mutations (loss of function) on the Patched, or activating mutations on smoothened (gain of function) can cause basal carcinomas, medulloblastomas, and rhabdomyosarcomas. |
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| Signalling by the Frizzled Receptors |
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Definition
| Wnt proteins are factors that represent another type of independent signalling system. They activate receptors of the frizzled (frz) family (multiple transmembrane domains). In the absence of ligand binding, a complex of Axin and Apc allow glycogen synthase kinase (GSK) to phosphorylate B-catenin (proliferation promoting protein) causing its degradation. In the presence of Wnt, B-catenin is spared and therefore promotes proliferation. |
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| Cell Surface receptors that use the components of the extracellular matrix as ligands. (to determine attachment to something to prevent anoikis). Having bound to ligands, these integrins form clusters known as focal adhesions. These prevent anoikis, link to cytoplasmic domains, and cause cytoplasmic domains to activate positive signaling pathways. |
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| Focal adhesion kinase. An important signaling molecule that associated with the cytoplasmic domain of integrins. Signals transduced by the FAK are important for reconfiguring shape, motility, and adhesion. |
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| Increased Cell Migration using FAK and v-Src in vitro |
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| With over expression of FAK, there is an increase in cell migration, as well as with the presents of Src-RT. FAK and Src are dependent on each other, minimal growth without one or the other. |
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| G protein that causes the abrogation of the 2 (presence of mitogenic growth factors and sufficient anchorage) preconditions that need to be satisfied before division and growth can occur. |
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| Ras binds gdp in its inactive state, and gtp in its active, signal-emitting state. The inactive Ras protein is stimulated by a guanine exchange (GEF) factor. This caused the release its GDP and aquire a GTP. This is halted by a GTPase activating protein (GAP) which hydrolyzes the GTP to GDP. Amino acid subsitutions caused by an oncogenic mutation can block GAP, leaving Ras in a perpetually active state. |
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| Ras has many roles in cellular functions, namely in terms of cytoskeleton cell motility, apoptosis, and cell-cycle progression. |
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| Potential of Unregulated Ras cycle |
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| The mitogen activated protein kinase pathway is downstream from the Ras pathway, so an unregulated Ras protein can ultimately lead to unregulated MAP pathways. The Ras protein activated the MAP kinase kinase kinase(Raf), which phosphorylate the MAP kinase Kinase, (Mek [MapK/ErkK]), which stimulates the MAP Kinase (Erk [extracellular signal-regulated kinases]) This ultimately can lead to changes in protein activity or changes in gene expression. |
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| Myc relation to Ras/Raf Pathway |
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Definition
| After cascade of MAP kinases, the MAP Kinase activates a gene reulatory protein which activated the myc gene to produce Myc |
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| Synergystic Oncogene effects |
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| The presence of both myc and ras cause a drecrease in the percentage of tumor free mice |
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| Cross talk does occur in the MAPK pathway, in other words there is more than 1 pathway to a given gene expression,. |
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