G-protein beta/gamma signaling
G proteins are critical cellular signal transducers for a variety of
cell surface receptors. G-protein coupled receptors interact
with the trimeric G-protein alpha-s/beta/gamma complex and
trigger the exchange of GDP to GTP bound to G-protein alpha
subunits leading to the dissociation of beta/gamma
heterodimers.
Both G-protein alpha and
G-protein beta/gamma subunits of complex are able to
transduce receptor signaling independently as well. For instance, G-protein
beta/gamma subunits regulate caveolae-mediated endocytosis activity and
transendothelial albumin transport via transcytosis by inducing v-src sarcoma
(Schmidt-Ruppin A-2) viral oncogene homolog
(c-Src)-mediated tyrosine phosphorylation and
subsequent association of endocytic traffic proteins, Caveolin 1, caveolae protein, 22kDa
(Caveolin-1) and Dynamin-2
[1].
Another function of G-protein beta/gamma
subunits is the activation of Mitogen-activated protein kinase 1-3
(ERK1/2) pathway via the c-Src
activation where c-Src activates
ERK1/2 through phosphorylation of adaptor protein SHC (Src
homology 2 domain containing) transforming protein 1 (Shc),
and recruitment of adaptor protein Growth factor receptor-bound protein 2
(GRB2) and Son of sevenless homolog
(SOS).
G-protein beta/gamma signaling also
regulates phosphoinositide metabolism by increasing the kinase activity of Bruton
agammaglobulinemia tyrosine kinase (Btk), a known activator
of Phospholipase C, gamma (PLC-gamma) [2] or by
direct activation of Phospholipase C, beta 2 (PLC-beta2).
PLC-gamma and PLC-beta2
catalyze hydrolysis of phosphoinositide 4,5-bisphosphate
(PtdIns(4,5)P2) to form inositol 1,4,5-triphosphate
(IP3) and 1,2-diacyl-glycerol
(DAG). The G-protein
beta/gamma heterodimers also activate
Phosphoinositide-3-kinase, regulatory subunit 5 (PI3K reg class IB
(p101)) that leads to Phosphoinositide-3-kinase, catalytic, gamma
polypeptide (PI3K cat class IB (p110-gamma)) -mediated
conversion of phosphatidylinositol 4,5-biphosphate
(PtdIns(4,5)P2) to phosphatidylinositol 3,4,5-triphosphate
(PtdIns(3,4,5)P3) [3].
PtdIns(3,4,5)P3 is a second messenger that directly binds to
3-phosphoinositide dependent protein kinase-1 (PDK(PDPK1))
and V-akt murine thymoma viral oncogene homolog 1
(AKT(PKB)). PDK(PDPK1)
phosphorylates AKT(PKB) and activates
AKT signaling [4].
G-proteins beta/gamma can regulate Adenylate cyclase 2
(Adenylate cyclase type II) and Adenylate cyclase 5
(Adenylate cyclase type V) activity. Adenylate
cyclases increase level of cAMP in cells and
activate Protein kinase, cAMP-dependent, regulatory (PKA-reg
(cAMP-dependent)) that results in Protein
kinase, cAMP-dependent, catalytic (PKA-cat (cAMP-dependent))
activation [5].
Regulator of G-protein signaling 3 (RGS3)
binds G-protein beta/gamma subunits and limits their ability
to trigger the production of inositol phosphates and the activation of
AKT(PKB) and ERK1/2 signaling
[6].
References:
- Shajahan AN, Tiruppathi C, Smrcka AV, Malik AB, Minshall RD
Gbetagamma activation of Src induces caveolae-mediated endocytosis in endothelial cells.
The Journal of biological chemistry 2004 Nov 12;279(46):48055-62
- Lowry WE, Huang XY
G Protein beta gamma subunits act on the catalytic domain to stimulate Bruton's agammaglobulinemia tyrosine kinase.
The Journal of biological chemistry 2002 Jan 11;277(2):1488-92
- Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer.
Annual review of cell and developmental biology 2001;17:615-75
- Igarashi J, Michel T
Sphingosine 1-phosphate and isoform-specific activation of phosphoinositide 3-kinase beta. Evidence for divergence and convergence of receptor-regulated endothelial nitric-oxide synthase signaling pathways.
The Journal of biological chemistry 2001 Sep 28;276(39):36281-8
- Defer N, Best-Belpomme M, Hanoune J
Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase.
American journal of physiology. Renal physiology 2000 Sep;279(3):F400-16
- Shi CS, Lee SB, Sinnarajah S, Dessauer CW, Rhee SG, Kehrl JH
Regulator of G-protein signaling 3 (RGS3) inhibits Gbeta1gamma 2-induced inositol phosphate production, mitogen-activated protein kinase activation, and Akt activation.
The Journal of biological chemistry 2001 Jun 29;276(26):24293-300
