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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

Activation of G proteins by GIV-GEF modulates multi-receptor signaling and broadly impacts the downstream signaling networkSchematic showing the diverse classes of receptors (upper half) which sense a variety of chemical signals, that converge on GIV. Lower part shows the consequence of non-canonical transactivation of G proteins by GIV (when GIV-GEF is functionally intact or turned "ON") on the multitude of downstream pathways within the signaling network. Green = enhancement; Red = suppression. Shown in the middle are three known ways to either inhibit (PKCθ selectively phosphoinhibits GIV-GEF [27]; SHP-1 dephosphorylates tyrosine-phosphorylated GIV [30]) or activate (CDK5 phosphoactivates GIV-GEF [37]) GIV-dependent signaling.
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Figure 1: Activation of G proteins by GIV-GEF modulates multi-receptor signaling and broadly impacts the downstream signaling networkSchematic showing the diverse classes of receptors (upper half) which sense a variety of chemical signals, that converge on GIV. Lower part shows the consequence of non-canonical transactivation of G proteins by GIV (when GIV-GEF is functionally intact or turned "ON") on the multitude of downstream pathways within the signaling network. Green = enhancement; Red = suppression. Shown in the middle are three known ways to either inhibit (PKCθ selectively phosphoinhibits GIV-GEF [27]; SHP-1 dephosphorylates tyrosine-phosphorylated GIV [30]) or activate (CDK5 phosphoactivates GIV-GEF [37]) GIV-dependent signaling.

Mentions: Despite the insights gained, the rare oncogenic driver mutations in G proteins in a handful of cancers do not explain the basis for deregulated G protein signaling in the vast majority of cancers that do not harbor mutant G or GPCR proteins. A growing body of work by us and others [24, 45, 46] have indicated that genetic or epigenetic factors that deregulate the intricate network of G protein regulatory proteins are just as significant as those that directly affect the G proteins /GPCRs, if not more. More specifically, a recently identified family of non-receptor GEFs, called rheostats [35] best exemplify the wide prevalence and broad significance of deregulated G protein regulatory network in cancers. Rheostats like GIV (Gα-Interacting Vesicle-associated; a.k.a Girdin) [24] and other members of this family, are non-receptor GEFs for trimeric G proteins; they derive their name based on their ability to 'adjust' the duration of G protein signaling depending on the abundance of functional copies of the GEF in cells [35]. Studies on GIV-GEF have led to the rapid emergence of a new paradigm in non-canonical activation of trimeric G proteins that has distinctive temporal and spatial features. Such activation appears to be less constrained and less restricted than canonical G protein activation by receptor GEFs (i.e., GPCRs) in three major ways (summarized in [24]): 1) G proteins can be transactivated by diverse classes of receptors, e.g., growth factor RTKs, TLRs, integrins and GPCRs--many of which are typically not known to bind or activate G proteins; 2) G proteins both at the PM and on internal membranes that are discontinuous with the PM can be activated; and 3) Activation continues for prolonged periods of time (as opposed to milliseconds). While the molecular mechanisms that govern such non-canonical G protein activation and the variety of pathways it modulates (summarized in Figure 1) are still unfolding, the relevance of this new paradigm in cancer and other diseases is clear (summarized in [24]).


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)

Activation of G proteins by GIV-GEF modulates multi-receptor signaling and broadly impacts the downstream signaling networkSchematic showing the diverse classes of receptors (upper half) which sense a variety of chemical signals, that converge on GIV. Lower part shows the consequence of non-canonical transactivation of G proteins by GIV (when GIV-GEF is functionally intact or turned "ON") on the multitude of downstream pathways within the signaling network. Green = enhancement; Red = suppression. Shown in the middle are three known ways to either inhibit (PKCθ selectively phosphoinhibits GIV-GEF [27]; SHP-1 dephosphorylates tyrosine-phosphorylated GIV [30]) or activate (CDK5 phosphoactivates GIV-GEF [37]) GIV-dependent signaling.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Activation of G proteins by GIV-GEF modulates multi-receptor signaling and broadly impacts the downstream signaling networkSchematic showing the diverse classes of receptors (upper half) which sense a variety of chemical signals, that converge on GIV. Lower part shows the consequence of non-canonical transactivation of G proteins by GIV (when GIV-GEF is functionally intact or turned "ON") on the multitude of downstream pathways within the signaling network. Green = enhancement; Red = suppression. Shown in the middle are three known ways to either inhibit (PKCθ selectively phosphoinhibits GIV-GEF [27]; SHP-1 dephosphorylates tyrosine-phosphorylated GIV [30]) or activate (CDK5 phosphoactivates GIV-GEF [37]) GIV-dependent signaling.
Mentions: Despite the insights gained, the rare oncogenic driver mutations in G proteins in a handful of cancers do not explain the basis for deregulated G protein signaling in the vast majority of cancers that do not harbor mutant G or GPCR proteins. A growing body of work by us and others [24, 45, 46] have indicated that genetic or epigenetic factors that deregulate the intricate network of G protein regulatory proteins are just as significant as those that directly affect the G proteins /GPCRs, if not more. More specifically, a recently identified family of non-receptor GEFs, called rheostats [35] best exemplify the wide prevalence and broad significance of deregulated G protein regulatory network in cancers. Rheostats like GIV (Gα-Interacting Vesicle-associated; a.k.a Girdin) [24] and other members of this family, are non-receptor GEFs for trimeric G proteins; they derive their name based on their ability to 'adjust' the duration of G protein signaling depending on the abundance of functional copies of the GEF in cells [35]. Studies on GIV-GEF have led to the rapid emergence of a new paradigm in non-canonical activation of trimeric G proteins that has distinctive temporal and spatial features. Such activation appears to be less constrained and less restricted than canonical G protein activation by receptor GEFs (i.e., GPCRs) in three major ways (summarized in [24]): 1) G proteins can be transactivated by diverse classes of receptors, e.g., growth factor RTKs, TLRs, integrins and GPCRs--many of which are typically not known to bind or activate G proteins; 2) G proteins both at the PM and on internal membranes that are discontinuous with the PM can be activated; and 3) Activation continues for prolonged periods of time (as opposed to milliseconds). While the molecular mechanisms that govern such non-canonical G protein activation and the variety of pathways it modulates (summarized in Figure 1) are still unfolding, the relevance of this new paradigm in cancer and other diseases is clear (summarized in [24]).

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