Bioc 460 Spring 1999
Lecture 40 - Chapter 13

- Glucocorticoid regulation of PEPCK expression
- Membrane receptor tyrosine kinases
- Defects in hormone signaling pathways

Glucocorticoids play a major role in stimulating gluconeogenesis in the liver. All steroids function by binding to intracellular receptor proteins that regulate the transcription of specific genes within the cell nucleus. Stimulation of phosphoenol pyruvate carboxykinase (PEPCK) gene transcription by the glucocorticoid receptor is an example of steroid hormone action. PEPCK catalyzes the conversion of oxaloacetate to pyruvate in the gluconeogenic pathway.

1. Glucocorticoids enter cells and bind to the glucocorticoid receptor (GR) protein.

RLM 40.1

2. The GR protein induces transcription of the PEPCK gene by binding to DNA as a dimer.

RLM 40.2

3. Regulation of the PEPCK gene is very complex and involves multiple protein-protein interactions.

RLM 40.3

The binding of hormones and growth factors, such as insulin and epidermal growth factor, to membrane-bound receptors, initiates a cascade of phosphorylation events culminating in alterations in cellular processes. The binding of ligands to the extracellular domain of receptor tyrosine kinases causes a conformational change in the receptor. In most cases, this ligand-induced conformation change stimulates receptor dimerization and autophosphorylation.

Figure 13.48

Figure 13.49

The epidermal growth factor (EGF) receptor is a well-studied example of a receptor tyrosine kinase. Binding of EGF to the receptor leads to receptor dimerization and autophosphorylation. The phosphorylated EGF receptor interacts with target proteins through phosphotyrosine residues which serve as binding sites. The target proteins are phosphorylated by the receptor kinase and then disengage. Chimeric receptor molecules have been created to investigate the molecular mechanism of EGF receptor function. SH2 and SH3 domains are conserved amino acid sequences that function as docking sites for receptor tyrosine kinase and their respective target proteins.

Figure 13.51

Figure 13.52

Figure 13.53

Figure 13.54

Many types of cancer genes (oncogenes) have been discovered based on their altered expression, activity or conspicuous absence in cancer cells. One of the first types to be discovered was called "src" (pronounced "sark") which turned out to be a cytosolic tyrosine kinase that is normally under tight control. In cancer cells, the mutated src protein is always active and as a result stimulates cells to divide through an aberrant phosphorylation cascade. Many of these cancer genes were first discovered in viruses that had "captured" host genes and exploited their growth controlling activities.

Table 13.4

Figure 13.56

Another important cancer gene is called "ras", which encodes a GTPase protein involved in signal transduction. Normally ras serves as a signal effector protein that functions by interacting with cytosolic proteins regulating the activation cellular kinases that control cell proliferation. This effector function of ras is activated by GTP binding and inactivated by GTP hydrolysis (the GDP bound form of ras is inactive). The mutated form of ras found in many types of cancer cells is always active due to a mutation in its intrinsic GTPase activity. The net result of this mutation is analogous to a gas peddle being stuck in the "on" position. Most importantly, the downstream kinase signal which responds to ras, and is reponsible for control of cell proliferation, is constitutively activated!

Figure 13.59

Page 355

RLM 40.4

---

Return to List of Bioc 460 Lectures

---

Department of Biochemistry The University of Arizona Spring 1999  RLM@u.arizona.edu cusanovi@u.arizona.edu http://www.biochem.arizona.edu/classes/bioc460/spring/springindex.html All contents copyright © 1999. All rights reserved.