G protein coupled receptor transactivation: extending the paradigm to include serine/threonine kinase receptors.
The current paradigm of G protein coupled receptor signaling involves a classical pathway being the activation of phospholipase C and the generation of 1,4,5-inositol trisphosphate, signaling through β-arrestin scaffold molecules and the transactivation of tyrosine kinase growth factor receptors. Transactivation greatly expands the range of signaling pathways and responses attributable to the receptor. Recently it has been revealed that G protein coupled receptor agonists can also transactivate the serine/threonine kinase cell surface receptor for transforming growth factor-β (Alk5). This leads to the generation of carboxyl terminal phosphorylated Smad2 which is the immediate downstream product of the activated Alk5. Thus, the current paradigm of G protein coupled signaling can be expanded to include the transactivation of the serine kinase receptor Alk5. These insights expand the possibilities for outcomes of therapeutically targeting GPCRs where more substantive and prolonged actions such as the synthesis of extracellular matrix may be affected.
BakerIDI Heart and Diabetes Institute, Commercial Road, Melbourne, Victoria 3004, Australia.
Micah L
ML
Burch
Narin
N
Osman
Robel
R
Getachew
Sefaa
S
Al-Aryahi
Philip
P
Poronnik
Wenhua
W
Zheng
Michael A
MA
Hill
Peter J
PJ
Little
D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics*; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism; D000071557:beta-Arrestins
D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D000071557:beta-Arrestins; D015544:Inositol 1,4,5-Trisphosphate; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; D010738:Type C Phospholipases