Monday, 18th December 2017
Cell Biology and Immunology
G protein-coupled receptor networks: signal transduction and pathophysiological implications

 

 


Grupo-400

 


Federico Mayor Jr.

ASciStaff

APublications

 

Research summary:

Our laboratory is investigating key nodes in signalling networks involved in prevalent age-related pathologies such as metabolic/cardiovascular diseases and cancer. The GRK2 kinase is one of those key signalling hubs. In addition to its canonical role as a regulator of G protein-coupled receptors (GPCR), GRK2 can also impact cell signalling networks by directly interacting and/or phosphorylating non-GPCR components of Federico Mayor Fig1transduction cascades (such as HDAC6, IRS1, PI3K, EPAC, Mdm2, Smads or p38 Mapk). Such integrated interactions underlie the participation of GRK2 in the control of cell migration, angiogenesis or insulin resistance (IR).

GRK2 levels/activity are altered in human pathologies such as cancer, inflammation and cardiovascular/ metabolic diseases related to IR. We seek to understand how concurrent changes in GRK2 levels (involving different cell types and tissues) integrate at the cellular and organism level, and how they can foster disease progression, by using cellular and animal models (including hemizygous, conditional and tissue-specific GRK2-deficient animals).

We investigate how changes in GRK2 expression in different tumor cell types (tumoral, macrophages and endothelial cells) might act synergistically to promote different aspects of tumor progression (proliferation, survival, senescence, genomic stability, angiogenesis, metastatic invasion) by modulating either GPCRs, the HDAC6 or the Mdm2/p53 sFederico Mayor Fig2ignaling axis, among others.

On the other hand, we analyzwe the GRK2 hub as a central integrator of signaling cascades relevant to IR-related pathologies and co-morbidities in different tissues and cell types (adipose, liver, pancreas, heart, macrophages/immune cells), by simultaneously modulating both the insulin cascade and key GPCRs controlling metabolic homeostasis, nutrient sensing or insulin secretion/sensitivity.

Other signaling node related to GRK2 is Gαq. We have unveiled novel interactions of Gαq with PB1-domain containing proteins such as PKCζ, and we are investigating the functional impact of this new Gαq interactome in cell death, autophagy and oxidative stress processes and in the development of cardiovascular diseases.

 


 

Patents:

  • New phosphorylation site of mitogen-activated protein kinases, modified proteins and applications EP 1899461B1 /WO 2007/028430 Awarded 2010
  • p38 inhibitor peptides and applications. PCT/ES2011/070774.
  • Protection of the effects of p38 inhibitory compounds. PCT/ES2012/070762