GDNF family signaling
Glial cell line-derived neurotrophic factors (GDNF family), a group of structurally
and functionally related polypeptides are involved in the control of neuron survival and
differentiation, kidney morphogenesis, and spermatogonial cell fate .
GDNF family ligands include GDNF, Neurturin
(NRTN), Artemin (ARTN) and
Persephin (PSPN). They signal through GDNF family receptor
alpha (GFRalpha), and Ret proto-oncogene
(RET) with tyrosine kinase activity. Four different
GFRalpha receptors have been characterized
GFRalpha4), which determine the ligand specificity of the
GDNF binds to GFRalpha1, then
forms a complex with RET. NRTN
binds to GFRalpha2, ARTN to
GFRalpha3, and PSPN activates
RET by binding to GFRalpha4.
NRTN and ARTN can crosstalk
weakly with GFRalpha1, and GDNF
with GFRalpha2. GDNFs bind to
lipid-anchored GFRalpha and induce
RET homodimerization and tyrosine autophosphorylation. Once
phosphorylated, tyrosine residues in the intracellular domain of activated
RET serve as high affinity binding sites for various
intracellular signaling proteins in the target cells, such as adaptor
proteins SHC transforming protein
(Shc), Fibroblast growth factor receptor substrate 2
(FRS2), Downstream of tyrosine kinase 1
(DOK1), Downstream of tyrosine kinase 4 and 5 (IRS5(DOK4)
and IRS6(DOK5)), Insulin receptor substrate 1 and 2 (IRS-1
and IRS-2) and PDZ and LIM domain 7 (ENIGMA).
RET can also recruit
Phospholipase C gamma (PLC-gamma) and V-src
sarcoma viral oncogene homolog (c-Src) .
RET activates several intracellular signaling cascades,
which regulate cell survival, differentiation, proliferation, migration, chemotaxis,
branching morphogenesis, neurite outgrowth, and synaptic plasticity.
Activation of RET initiates signal transduction pathways
via adaptor protein. Activation of Extracellular signal-regulated kinases
(ERK) pathway (with presumable molecular signal participants
v-Ha-ras Harvey rat sarcoma viral oncogene homolog
(H-RAS)/V-raf-1 murine leukemia viral oncogene homolog
(c-Raf)/ Mitogen-activated protein kinase kinase 1 and 2
MEK2)/ERK) occurs through
recruitment of Son of sevenless homolog
(SOS) by Growth factor receptor-bound protein
2 (GRB2)/ SHC transforming protein
(Shc) adaptor proteins.
Interaction of Shc with Gab2
and with regulatory subunits of Phosphoinositide-3-kinase (PI3K reg class
IA (p85)) results in activation of PI3K/V-akt
murine thymoma viral oncogene homolog 1 (AKT(PKB)) pathway
leading to cell survival .
Activation of the PI3K/AKT and Ras/ERK pathways results in the activation of two
transcription factors, Nuclear factor kappaB
(NF-kB) and cAMP responsive
element binding protein 1 (CREB1), respectively .
DOK1 is a docking protein for the
RET tyrosine kinase. DOK1
recruits GTPase activating protein RAS p21 protein activator
1 (p120GAP), which increase hydrolysis and inactivates
H-Ras. Hereby DOK1 participates
in attenuation of ERK activation. On the other hand
DOK1 bounds to the NCK adaptor protein 1
(NCK1) adaptor protein leads to Mitogen-activated protein
kinase 8, 9 and 10 (JNK(MAPK8-10)) and Jun oncogene
(c-Jun) activation .
- Airaksinen MS, Saarma M
The GDNF family: signalling, biological functions and therapeutic value.
Nature reviews. Neuroscience 2002 May;3(5):383-94
- Besset V, Scott RP, Iba?ez CF
Signaling complexes and protein-protein interactions involved in the activation of the Ras and phosphatidylinositol 3-kinase pathways by the c-Ret receptor tyrosine kinase.
The Journal of biological chemistry 2000 Dec 15;275(50):39159-66
- Kurokawa K, Kawai K, Hashimoto M, Ito Y, Takahashi M
Cell signalling and gene expression mediated by RET tyrosine kinase.
Journal of internal medicine 2003 Jun;253(6):627-33
- Murakami H, Yamamura Y, Shimono Y, Kawai K, Kurokawa K, Takahashi M
Role of Dok1 in cell signaling mediated by RET tyrosine kinase.
The Journal of biological chemistry 2002 Sep 6;277(36):32781-90