Trk receptors are a family of three receptor tyrosine kinases, each of which can be activated by one or more of four neurotrophins-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4 (NT3 and NT4). Neurotrophin signaling through these receptors regulates cell survival, proliferation, the fate of neural precursors, axon and dendrite growth and patterning, and the expression and activity of functionally important proteins, such as ion channels and neurotransmitter receptors. In the adult nervous system, the Trk receptors regulate synaptic strength and plasticity. The cytoplasmic domains of Trk receptors contain several sites of tyrosine phosphorylation that recruit intermediates in intracellular signaling cascades. As a result, Trk receptor signaling activates several small G proteins, including Ras, Rap-1, and the Cdc-42-Rac-Rho family, as well as pathways regulated by MAP kinase, PI 3-kinase and phospholipase-C-gamma (PLC-gamma). Trk receptor activation has different consequences in different cells, and the specificity of downstream Trk receptor-mediated signaling is controlled through expression of intermediates in these signaling pathways and membrane trafficking that regulates localization of different signaling constituents. Perhaps the most fascinating aspect of Trk receptor-mediated signaling is its interplay with signaling promoted by the pan-neurotrophin receptor p75NTR. p75NTR activates a distinct set of signaling pathways within cells that are in some instances synergistic and in other instances antagonistic to those activated by Trk receptors. Several of these are proapoptotic but are suppressed by Trk receptor-initiated signaling. p75NTR also influences the conformations of Trk receptors; this modifies ligand-binding specificity and affinity with important developmental consequences.

Trk receptors: roles in neuronal signal transduction.

Members of the nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) families — comprising neurotrophins and GDNF-family ligands (GFLs), respectively — are crucial for the development and maintenance of distinct sets of central and peripheral neurons. Knockout studies in the mouse have revealed that members of these two families might collaborate or act sequentially in a given neuron. Although neurotrophins and GFLs activate common intracellular signalling pathways through their receptor tyrosine kinases, several clear differences exist between these families of trophic factors.

The GDNF family: Signalling, biological functions and therapeutic value

Spermatogonial stem cells (SSCs) self-renew and produce large numbers of committed progenitors that are destined to differentiate into spermatozoa throughout life. However, the growth factors essential for self-renewal of SSCs remain unclear. In this study, a serum-free culture system and a transplantation assay for SSCs were used to identify exogenous soluble factors that promote proliferation of SSCs. Mouse pup testis cells were enriched for SSCs by selection with an anti-Thy-1 antibody and cultured on STO (SIM mouse embryo-derived thioguanine and ouabain resistant) feeders in a serum-free defined medium. In the presence of glial cell line-derived neurotrophic factor (GDNF), SSCs from DBA/2J strain mice formed densely packed clumps of cells and continuously proliferated. However, other strains of mice required the addition of soluble GDNF-family receptor α-1 and basic fibroblast growth factor to support replication. The functional transplantation assay proved that the clump-forming cells are indeed SSCs. Thus, GDNF-induced cell signaling plays a central role in SSC self-renewal. The number of SSCs in culture doubled every 5.6 days, and the clump-forming cells strongly expressed Oct-4. Under these conditions, SSCs proliferated over 6 months, reconstituted long-term spermatogenesis after transplantation into recipient testes, and restored fertility to infertile recipients. The identification of exogenous factors that allow continuous proliferation of SSCs in vitro establishes the foundation to study the basic biology of SSCs and makes possible germ-line modification by sophisticated technologies. Moreover, the ability to recover, culture indefinitely, and transplant SSCs will make the germ-line of individual males available for periods extending beyond a normal lifetime.

https://www.pnas.org/content/pnas/101/47/16489.full.pdf

Growth factors essential for self-renewal and expansion of mouse spermatogonial stem cells

We review the role of cadherins and cadherin-related proteins in human cancer. Cellular and animal models for human cancer are also dealt with whenever appropriate. E-cadherin is the prototype of the large cadherin superfamily and is renowned for its potent malignancy suppressing activity. Different mechanisms for inactivating E-cadherin/CDH1 have been identified in human cancers: inherited and somatic mutations, aberrant protein processing, increased promoter methylation, and induction of transcriptional repressors such as Snail and ZEB family members. The latter induce epithelial mesenchymal transition, which is also associated with induction of "mesenchymal" cadherins, a hallmark of tumor progression. VE-cadherin/CDH5 plays a role in tumor-associated angiogenesis. The atypical T-cadherin/CDH13 is often silenced in cancer cells but up-regulated in tumor vasculature. The review also covers the status of protocadherins and several other cadherin-related molecules in human cancer. Perspectives for emerging cadherin-related anticancer therapies are given.

/pdf/involvement-of-members-of-the-cadherin-superfamily-in-cancer-3zuzsjo3pt.pdf

Involvement of Members of the Cadherin Superfamily in Cancer

The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands.

https://carlosibanezlab.se/OUR_PAPERS/Paratcha_Neuron2001.pdf

Released GFRα1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts

https://carlosibanezlab.se/OUR_PAPERS/Anders_JBC2001.pdf

Molecular Modeling of the Extracellular Domain of the RET Receptor Tyrosine Kinase Reveals Multiple Cadherin-like Domains and a Calcium-binding Site

The catalytic and signaling activities of RET, a tyrosine kinase receptor for glial cell line-derived neurotrophic factor (GDNF), are controlled by the autophosphorylation of several tyrosine residues in the RET cytoplasmic domain. To analyze the phosphorylation state of individual tyrosines, we generated antibodies recognizing specific phosphotyrosine sites involved in the catalytic (Tyr 905 ) and downstream signaling (Tyr 1015 , Tyr 1062 , and Tyr 1096 ) activities of this receptor. Stimulation with GDNF induced coordinated phosphorylation of the 4 tyrosine residues in neuronal cell lines and in primary cultures of sympathetic neurons isolated from rat superior cervical ganglia. Neurturin and artemin, two other members of the GDNF ligand family, also induced synchronized phosphorylation of RET tyrosines with kinetics comparable to those observed with GDNF. Tyrosine phosphorylation was maximal 15 min after ligand stimulation, decaying thereafter with similar kinetics in all 4 residues. Co-stimulation with a soluble form of the GFR1 co-receptor potentiated ligand-dependent phosphorylation of different intracellular tyrosines to a similar extent and increased the survival of superior cervical ganglion neurons compared with treatment with GDNF alone. In vivo, high levels of phosphorylated Tyr 905 , Tyr 1015 , and Tyr 1062 were detected in embryonic mouse dorsal root ganglia, with a sharp decline at early postnatal stages. Protein transduction of anti-Tyr(P) 1062 antibodies into cultured cells reduced activation of MAPKs ERK1 and ERK2 and the AKT kinase in response to GDNF and diminished GDNF-dependent neuronal differentiation and survival of embryonic sensory neurons from the nodose ganglion. These results demonstrate synchronized utilization of individual RET tyrosine residues in neurons in vivo and reveal

Coordinated Activation of Autophosphorylation Sites in the RET

https://carlosibanezlab.se/OUR_PAPERS/Coulpier_JBC2002.pdf

Coordinated Activation of Autophosphorylation Sites in the RET Receptor Tyrosine Kinase IMPORTANCE OF TYROSINE 1062 FOR GDNF MEDIATED NEURONAL DIFFERENTIATION AND SURVIVAL

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Papers

Released GFRα1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts

Molecular Modeling of the Extracellular Domain of the RET Receptor Tyrosine Kinase Reveals Multiple Cadherin-like Domains and a Calcium-binding Site

Coordinated Activation of Autophosphorylation Sites in the RET

Coordinated Activation of Autophosphorylation Sites in the RET Receptor Tyrosine Kinase IMPORTANCE OF TYROSINE 1062 FOR GDNF MEDIATED NEURONAL DIFFERENTIATION AND SURVIVAL