Abstract/Details

Defining the role of heterotrimeric G-proteins in EGF receptor trafficking and signaling


2009 2009

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Abstract (summary)

RGS-PX1 functions as a GAP that inactivates Gαs and regulates EGFR trafficking and signaling, while GIV binds Gαi to form a molecular switch that and activates Gαi and promotes efficient receptor signaling. Yet the mechanisms by which Gαs/RGS-PX1 and Gαi/GIV affect EGFR signaling remained unclear. I set out to further define the roles of Gαs/RGS-PX1 and Gαi/GIV in EGFR trafficking and signaling.

We found that Gαs regulates EGFR degradation. Specifically, Gαs depletion by RNAi delayed and Gαs overexpression promoted EGF-induced degradation of EGFR, a key step in the downregulation of receptor signaling. In addition, Gαs and RGS-PX1 form a complex with Hrs, a component necessary for receptor sorting for degradation. Thus, Gαs promotes EGFR degradation and forms a complex with RGS-PX1 and Hrs that might be required for efficient receptor sorting. Gαs depletion also enhanced ligand-induced EGFR autophosphorylation and ERK 1/2 signaling, and a siRNA-resistant, inactive Gαs-G226A mutant but not an active Gαs-Q227L mutant reversed these effects. Together, these data indicate that activation of Gαs delays and inactivation of Gαs by RGS-PX1 promotes downregulation of EGFR signaling.

We also found that the Gαi-GIV switch reprograms EGFR signaling to influence whether cells migrate or proliferate. Specifically, GIV interacts with EGFR, and GIV’s GEF motif promotes several events including formation of a ligand-induced complex between EGFR, Gαi, and actin which promotes receptor signaling within the plasma membrane (PM)-actin bed, receptor autophosphorylation, PM-based signaling to Akt and PLCγ, and cell migration. Disabling GIV’s GEF motif by mutation (GIV-F1685A) disrupts this complex which promotes receptor signaling trafficking from endosomes, inhibits receptor autophosphorylation, and enhances endosome-based signaling to ERK 1/2 MAPK and c-Src/STAT5b and cell proliferation. Furthermore, early during progression of colorectal carcinomas, before metastatic invasion the Gαi-GIV switch is disabled due to the loss of GIV’s carboxy-terminus and critical GEF motif by alternative splicing. Later during metastatic invasion the switch is assembled by upregulation of GIV. Therefore, the switch is selectively assembled or not at different stages of oncogenesis leading to promigration or proliferative cellular profiles, respectively. These traits might cumulatively influence growth and invasiveness of tumors during oncogenic progression.

Indexing (details)


Subject
Cellular biology
Classification
0379: Cellular biology
Identifier / keyword
Biological sciences; Cell migration; Cell proliferation; EGFR; Heterotrimeric G-proteins; Trafficking
Title
Defining the role of heterotrimeric G-proteins in EGF receptor trafficking and signaling
Author
Beas, Anthony O.
Number of pages
180
Publication year
2009
Degree date
2009
School code
0033
Source
DAI-B 70/09, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781109361865
Advisor
Farquhar, Marilyn Gist
Committee member
Brown, John H.; Desai, Arshad; Gill, Gordon N.; Insel, Paul A.; Taylor, Susan S.
University/institution
University of California, San Diego
Department
Biomedical Sciences
University location
United States -- California
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3372499
ProQuest document ID
304851769
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304851769
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