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Heterotrimeric G proteins as emerging targets for network based therapy in cancer: End of a long futile campaign striking heads of a Hydra.

Ghosh P - Aging (Albany NY) (2015)

Bottom Line: Recently, a rapidly emerging paradigm has revealed GIV/Girdin as a central platform for receptor cross-talk which integrates signals downstream of a myriad of cell surface receptors, and modulates several key pathways within downstream signaling network, all via non-canonical activation of trimeric G proteins.Unlike canonical signal transduction via G proteins, which is spatially and temporally restricted, the temporal and spatial features of non-canonical activation of G protein via GIV is unusually unrestricted.Consequently, the GIV●G protein interface serves as a central hub allowing for control over several pathways within the pathologic signaling network, all at once.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.

ABSTRACT
Most common diseases, e.g., cancer are driven by not one, but multiple cell surface receptors that trigger and sustain a pathologic signaling network. The largest fraction of therapeutic agents that target individual receptors/pathways eventually fail due to the emergence of compensatory mechanisms that reestablish the pathologic network. Recently, a rapidly emerging paradigm has revealed GIV/Girdin as a central platform for receptor cross-talk which integrates signals downstream of a myriad of cell surface receptors, and modulates several key pathways within downstream signaling network, all via non-canonical activation of trimeric G proteins. Unlike canonical signal transduction via G proteins, which is spatially and temporally restricted, the temporal and spatial features of non-canonical activation of G protein via GIV is unusually unrestricted. Consequently, the GIV●G protein interface serves as a central hub allowing for control over several pathways within the pathologic signaling network, all at once. The relevance of this new paradigm in cancer and other disease states and the pros and cons of targeting the GIV●G protein interface are discussed.

No MeSH data available.


Related in: MedlinePlus

GIV is a bona-fide prometastatic proteinSchematic summarizing the variety of solid tumors in which elevated expression of GIV/Girdin in tumor cells has been linked to its role in imparting stemness, invasiveness, prometastatic and anti-apoptotic signaling, aggressiveness and poor clinical outcome has been studied.
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Figure 2: GIV is a bona-fide prometastatic proteinSchematic summarizing the variety of solid tumors in which elevated expression of GIV/Girdin in tumor cells has been linked to its role in imparting stemness, invasiveness, prometastatic and anti-apoptotic signaling, aggressiveness and poor clinical outcome has been studied.

Mentions: Given the broad landscape of signaling pathways that GIV modulates, and its ubiquitous nature of expression, it is not surprising that deregulation of GIV-GEF drives several pathophysiologic conditions (Table). In the context of cancer, it is clear that high copies of GIV means unrestricted G protein signaling and propagation of signals that enhance tumorigenesis (like invasiveness, stemness and chemoresistance; [24], Table) regardless of the receptor of origin. Given the nature of receptor classes modulates and the prometastatic nature of the signaling pathways enhanced, GIV's expression at high levels carries a poor prognosis across a broad range of solid tumors (Figure 2). Although prometastatic signaling is the most well understood role of GIV, the striking yin-yang effect of GEF-ON versus GEF-OFF states has also been described in the context of some other cellular processes and diseases, e.g., fibrosis, wound healing, diabetes [24], most, if not all these diseases are also multi-receptor in origin (Table; green columns). It is possible that a similar yin-yang effect modulates all other diseases where GIV's role has been defined but the role of its GEF function has not (Table; red columns).


Heterotrimeric G proteins as emerging targets for network based therapy in cancer: End of a long futile campaign striking heads of a Hydra.

Ghosh P - Aging (Albany NY) (2015)

GIV is a bona-fide prometastatic proteinSchematic summarizing the variety of solid tumors in which elevated expression of GIV/Girdin in tumor cells has been linked to its role in imparting stemness, invasiveness, prometastatic and anti-apoptotic signaling, aggressiveness and poor clinical outcome has been studied.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543036&req=5

Figure 2: GIV is a bona-fide prometastatic proteinSchematic summarizing the variety of solid tumors in which elevated expression of GIV/Girdin in tumor cells has been linked to its role in imparting stemness, invasiveness, prometastatic and anti-apoptotic signaling, aggressiveness and poor clinical outcome has been studied.
Mentions: Given the broad landscape of signaling pathways that GIV modulates, and its ubiquitous nature of expression, it is not surprising that deregulation of GIV-GEF drives several pathophysiologic conditions (Table). In the context of cancer, it is clear that high copies of GIV means unrestricted G protein signaling and propagation of signals that enhance tumorigenesis (like invasiveness, stemness and chemoresistance; [24], Table) regardless of the receptor of origin. Given the nature of receptor classes modulates and the prometastatic nature of the signaling pathways enhanced, GIV's expression at high levels carries a poor prognosis across a broad range of solid tumors (Figure 2). Although prometastatic signaling is the most well understood role of GIV, the striking yin-yang effect of GEF-ON versus GEF-OFF states has also been described in the context of some other cellular processes and diseases, e.g., fibrosis, wound healing, diabetes [24], most, if not all these diseases are also multi-receptor in origin (Table; green columns). It is possible that a similar yin-yang effect modulates all other diseases where GIV's role has been defined but the role of its GEF function has not (Table; red columns).

Bottom Line: Recently, a rapidly emerging paradigm has revealed GIV/Girdin as a central platform for receptor cross-talk which integrates signals downstream of a myriad of cell surface receptors, and modulates several key pathways within downstream signaling network, all via non-canonical activation of trimeric G proteins.Unlike canonical signal transduction via G proteins, which is spatially and temporally restricted, the temporal and spatial features of non-canonical activation of G protein via GIV is unusually unrestricted.Consequently, the GIV●G protein interface serves as a central hub allowing for control over several pathways within the pathologic signaling network, all at once.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.

ABSTRACT
Most common diseases, e.g., cancer are driven by not one, but multiple cell surface receptors that trigger and sustain a pathologic signaling network. The largest fraction of therapeutic agents that target individual receptors/pathways eventually fail due to the emergence of compensatory mechanisms that reestablish the pathologic network. Recently, a rapidly emerging paradigm has revealed GIV/Girdin as a central platform for receptor cross-talk which integrates signals downstream of a myriad of cell surface receptors, and modulates several key pathways within downstream signaling network, all via non-canonical activation of trimeric G proteins. Unlike canonical signal transduction via G proteins, which is spatially and temporally restricted, the temporal and spatial features of non-canonical activation of G protein via GIV is unusually unrestricted. Consequently, the GIV●G protein interface serves as a central hub allowing for control over several pathways within the pathologic signaling network, all at once. The relevance of this new paradigm in cancer and other disease states and the pros and cons of targeting the GIV●G protein interface are discussed.

No MeSH data available.


Related in: MedlinePlus