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BENYA LAB: GASTRIN-RELEASING PEPTIDE RECEPTOR:
The gastrin-releasing peptide receptor (GRP-R) can cause the proliferation of many, but not all, cells in which it is expressed. This receptor is not normally expressed by epithelial cells lining the gastrointestinal (GI) tract; but is aberrantly expressed by many GI tumors. We are currently studying the extent and signficance of this receptor's expression by tumors of the stomach, pancreas, and colon. Although GRP clearly acts as a mitogen , our ongoing experiments also indicate that in vivo GRP predominantly acts as a morphogen in GI cancers.
Basic Science: Our primary focus is on the mechanisms regulating this receptor's desensitization, or being "turned off", after it has been activated. Our ongoing studies have shown that this receptor is desensitized by a mechanism that differs from the standard heptaspanning receptor paradigm. Specifically, whereas receptor phosphorylation by second messenger-independent kinases (i.e, bARK) is the traditional mechanism initiating heptaspanning desensitization, the GRP-R is turned off by a phosphorylation-independent process.
We are currently studying the role of phosphorylation to GRP-R function, as well as are attempting the define the mechanisms involved in its acute and chonic desensitization.
Clinical Science: The GRP-R is aberrantly expressed by GI cancers, and is believed to influence tumor cell proliferation. However, the growth-promoting mechanisms are not known. We are in the process of demonstrating by immunohistochemistry that >80% of colon cancers co-express both GRP and its receptor. Although this migh suggest that GRP could act as an autocrine growth factor, our data also suggests that this ligand acts as a morphogen.
We have shown that most aberrantly expressed GRP-R in gastric cancers are mutated, and that many mutations render this receptor constitutively active. Finally, we have also shown that the non-mutated wild type GRP-R can become constitutively active when aberrantly expressed in a non-malignant human colon epithelial cell line, and thereby cause cell proliferation. Thus at least 3 potential mechanisms exist that allow this receptor to act as an oncogene.
SELECTED REFERENCES:
Constitutive activation of the gastrin-releasing peptide receptor expressed by the non-malignant human colon epithelial cell line NCM460. J Clin Invest 1997: 100: 2530-2537.
Gastrin-releasing peptide is a mitogen and morphogen in murine colon cancer. Cell Growth Diff 2000; 11: 385-393.
The case for gastrin-releasing peptide acting as a morphogen when it and its receptor are aberrantly expressed in cancer. Peptides 2001; 22: 689-699 (a review).
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