Activation of Gαi at the Golgi by GIV/Girdin Imposes Finiteness in Arf1 Signaling

Lo, I-Chung; Gupta, Vijay; Midde, Krishna; Taupin, Vanessa; López-Sánchez, Inmaculada; Kufareva, Irina; Abagyan, Ruben; Randazzo, Paul A.; Farquhar, Marilyn G.; Ghosh, Pradipta

doi:10.1016/j.devcel.2015.02.009

Cited by 43 publications

(116 citation statements)

References 51 publications

(61 reference statements)

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“…Because CDK5 is activated within seconds after EGF stimulation (23), it is likely that once activated, CDK5 can promptly phosphorylate GIV at S1674 before or during the latter's recruitment to the activated receptor at the PM, ensuring maximal coupling to and activation of Gαi within 5 min after ligand stimulation. Because GIV-GEF has also been found to be functional on two types of intracellular membranes, e.g., triggers secretion from the Golgi (44) and inhibits the formation/maturation of autophagosomes (45), and because activation of CDK5 exerts similar effects on both processes (46,47), it is tempting to speculate that activation of GIV-GEF on internal membranes is also via CDK5. Further studies are required to determine if such is the case.…”

Section: Phosphorylation Of Giv At Ser1674 Modulates Egfr Signaling Andmentioning

confidence: 99%

Cyclin-dependent kinase 5 activates guanine nucleotide exchange factor GIV/Girdin to orchestrate migration–proliferation dichotomy

Bhandari

López-Sánchez

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Signals propagated by receptor tyrosine kinases (RTKs) can drive cell migration and proliferation, two cellular processes that do not occur simultaneously—a phenomenon called “migration–proliferation dichotomy.” We previously showed that epidermal growth factor (EGF) signaling is skewed to favor migration over proliferation via noncanonical transactivation of Gαi proteins by the guanine exchange factor (GEF) GIV. However, what turns on GIV-GEF downstream of growth factor RTKs remained unknown. Here we reveal the molecular mechanism by which phosphorylation of GIV by cyclin-dependent kinase 5 (CDK5) triggers GIV's ability to bind and activate Gαi in response to growth factors and modulate downstream signals to establish a dichotomy between migration and proliferation. We show that CDK5 binds and phosphorylates GIV at Ser1674 near its GEF motif. When Ser1674 is phosphorylated, GIV activates Gαi and enhances promigratory Akt signals. Phosphorylated GIV also binds Gαs and enhances endosomal maturation, which shortens the transit time of EGFR through early endosomes, thereby limiting mitogenic MAPK signals. Consequently, this phosphoevent triggers cells to preferentially migrate during wound healing and transmigration of cancer cells. When Ser1674 cannot be phosphorylated, GIV cannot bind either Gαi or Gαs, Akt signaling is suppressed, mitogenic signals are enhanced due to delayed transit time of EGFR through early endosomes, and cells preferentially proliferate. These results illuminate how GIV-GEF is turned on upon receptor activation, adds GIV to the repertoire of CDK5 substrates, and defines a mechanism by which this unusual CDK orchestrates migration–proliferation dichotomy during cancer invasion, wound healing, and development.

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Section: Phosphorylation Of Giv At Ser1674 Modulates Egfr Signaling Andmentioning

confidence: 99%

Cyclin-dependent kinase 5 activates guanine nucleotide exchange factor GIV/Girdin to orchestrate migration–proliferation dichotomy

Bhandari

López-Sánchez

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, evidence has recently been provided of non-canonical subcellular sites for G protein activation: these include endosomal localization of functionally active GPCR394041, and the interaction of the GIV/Girdin protein, a non-receptor guanine nucleotide exchange factor, with heterotrimeric G proteins at the Golgi4243 and at still undefined intracellular sites44. The effectiveness of N-myristoylated LANCL2 in coupling to G i physically and functionally (FRET efficiency and [cAMP] i increase, Fig.…”

Section: Discussionmentioning

confidence: 99%

G-protein coupling and nuclear translocation of the human abscisic acid receptor LANCL2

Fresia

Vigliarolo

Guida

et al. 2016

Sci Rep

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Abscisic acid (ABA), a long known phytohormone, has been recently demonstrated to be present also in humans, where it targets cells of the innate immune response, mesenchymal and hemopoietic stem cells and cells involved in the regulation of systemic glucose homeostasis. LANCL2, a peripheral membrane protein, is the mammalian ABA receptor. We show that N-terminal glycine myristoylation causes LANCL2 localization to the plasmamembrane and to cytoplasmic membrane vesicles, where it interacts with the α subunit of a Gi protein and starts the ABA signaling pathway via activation of adenylate cyclase. Demyristoylation of LANCL2 by chemical or genetic means triggers its nuclear translocation. Nuclear enrichment of native LANCL2 is also induced by ABA treatment. Therefore human LANCL2 is a non-transmembrane G protein-coupled receptor susceptible to hormone-induced nuclear translocation.

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“…Last, but not least, although tyrosine-based G protein signaling may appear to be a linear connection between input (the TKs) and output (G-proteins) elements (Figure 1), experimental data shows that it is rather an integral part of a network that links many receptors to many signaling pathways [summarized in (8)], and links multiple cellular organelles to events at the PM (19, 88). The behavior of such complex systems is hard to grasp by intuition.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

The untapped potential of tyrosine-based G protein signaling

Ghosh

2016

Pharmacological Research

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Tyrosine-based and trimeric G protein-based signaling are the two most widely studied and distinct mechanisms for signal transduction in eukaryotes. How each of them relay signals across the plasma membrane independently of each other has been extensively characterized; however, an understanding of how they work together remained obscure. Recently, a rapidly emerging paradigm has revealed that tyrosine based signals are relayed via G proteins, and that the crosstalk between the two hubs are more robustly and sophisticatedly integrated than was previously imagined. More importantly, by straddling the two signaling hubs that are most frequently targeted for their therapeutic significance, the tyrosine-based G-protein signaling pathway has its own growing list of pathophysiologic importance, both as therapeutic target in a variety of disease states, and by paving the way for personalized medicine. The fundamental principles of this emerging paradigm and its pharmacologic potential are discussed.

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Activation of Gαi at the Golgi by GIV/Girdin Imposes Finiteness in Arf1 Signaling

Cited by 43 publications

References 51 publications

Cyclin-dependent kinase 5 activates guanine nucleotide exchange factor GIV/Girdin to orchestrate migration–proliferation dichotomy

Cyclin-dependent kinase 5 activates guanine nucleotide exchange factor GIV/Girdin to orchestrate migration–proliferation dichotomy

G-protein coupling and nuclear translocation of the human abscisic acid receptor LANCL2

The untapped potential of tyrosine-based G protein signaling

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