Advanced Molecular Genetics-Biology 566
Signaling Pathways Operated by Receptor Protein Tyrosine Kinases
Tyrosine Kinase-containing Receptors
Anatomy of tyrosine kinase families:
Crosslinking of receptors causes activation.
Activation of PLC gamma results in the generation of DAG and IP3 which subsequently activates PKC and the release of Ca2+.
Activation of PKC in the dephosphorylation of cJun with the subsequent activation TREs.
Activation of Grb2 results in the binding of the GTP exchange factor SOS which facilitates the activation of Ras and the MAP pathway.
Activation can facilitate complex formation and additional modification that would not otherwise occur. For example, v-Abl adds a phosphate to p130 but only in the presence of an activated receptor can v-Abl and p130 bind adjacent to each other in such an orientation that will allow the addition of further phosphates on p130.
What are some of the active domains for binding and kinase/phosphatase activity?
Example of SH2 binding site.
Branching of the signalling pathway
A number of signal transduction pathways branch out from the receptor signalling complex.
Some of the pathways that we have seen are illustrated below.
Ras-Map kinase pathway
A closer look at the Ras-MAP kinase pathway activation by receptor protein tyrosine kinases show that not only is the Serum Response Element (SRE) activated but translation is also enhanced.
Mitogenic sigalling increases the rate of translation of selective mRNAs. ERK plays a role in initiating protein synthesis by phosphorylating Mnk1 which results in the removal of secondary structure at the initiation site for protein synthesis. Mnk1 is also the target for some viruses when hijacking cellular protein synthesis. For example, adenovirus protein p100 binds eIFG and displaces Mnk1 so that it is no longer able to activate eIF-4E. As a result, cellular mRNA remains untranslated while viral mRNA is unaffected and, as a result, the cell switches to the manufacture of viral proteins.
MAP kinases are actually a family of protein kinases that are widely distributed and are are found in all eukaryotic organisms.
These can be classified into three main functional groups. The first is mediated by mitogenic and differentiation signals. The other two respond to stress and inflammatory cytokines.
The ERK pathway responds to mitogen activation.
In the JNK/SAPK pathway SAPK stands for stress activation protein kinase and within this class of kinases the Jun N-terminal kinases (JNK) for a subfamily.
In the p38/HOG pathway HOG stands for high osmolarity glycerol where the p38 proteins are a subfamily.
Each of these pathways lead to the dual phosphorylation of MAP kinase family members responsible for activation of transcription factors.
We have looked at the control that phosphatases have on activation of the STAT pathway:
Here is the STAT pathway:
Additional G-protein activation of MAP kinase pathway
The Heparin-binding EGF-like growth factor, HB-EGF, exists as a membrane-bound precursor and when released through the activation of a metalloproteinase, it serves as a mitogen to activate a MAP kinase pathway.
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