Casaubon,
Thanks for discussion.
<<Are you asking if Timcodar promotes neurite outgrowth directly, or requires a FKBP mediated binding event? >>
Not directly. It is *promoting* effect, what we are talking about. So, if it isn't by interactions with any FK506 ligands, than what it is? As you said it is from VRTX FKBP library, still it is not FKBP-12 active.
<<I doubt Timcodar functions directly on neurite outgrowth as the presence of NGF is necessary to promote nerve growth.
Whether or not it is an FKBP mediated event is debateable.>>
The question is what FK506 mediated mechanisms (other than calcineurin-depended) promote growth. Gold work indicate that BP-12 isn't the only one, and they pointed to several path. Maybe, and most likely, there is more to come.
But for now one open possibility is mature GR effects on TGF-1 (known for neuron injury regenerator):
<<In human neuroblastoma SH-SY5Y cells, the neurotrophic action of FK506 (10 pM to 10 nM) is completely prevented by the addition of a monoclonal antibody (50-100 nM) to the immunophilin FKBP-52 (also known as FKBP-59 or heat shock protein 56), a component of mature steroid receptor complexes. >>
Proc Natl Acad Sci U S A 1999 Oct 12;96(21):11776-81
Glucocorticoid receptor inhibits transforming growth factor-beta signaling by directly targeting the transcriptional activation function of smad3.
Song CZ, Tian X, Gelehrter TD
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109-0618, USA.
[Medline record in process]
The transforming growth factor-beta (TGF-beta) family of cytokines and glucocorticoids regulate diverse biological processes through modulating the expression of target genes. Here we report that glucocorticoid receptor (GR) represses TGF-beta transcriptional activation of the type-1 plasminogen activator inhibitor (PAI-1) gene in a ligand-dependent manner. Similarly, GR represses TGF-beta activation of the TGF-beta responsive sequence containing Smad3/4-binding sites. Using mammalian two-hybrid assays, we demonstrate that GR inhibits transcriptional activation by both Smad3 and Smad4 C-terminal activation domains. Finally, we show that GR interacts with Smad3 both in vitro and in vivo. These results suggest a molecular basis for the cross-regulation between glucocorticoid and TGF-beta signaling pathways.
However, after hrNGF failed in DN PIII trials (Genentech blaimed too low drug dose) nobody believe that neuroiphilin ligand will work by itself. Unless the drug itself can mediate increase in endogenous NGF level or mimic its activity, which isn't that unlikely by cross-interaction and cross-dependence, present in many signaling events. I can't said that it will, but Timcodor did have promising results in PD and DN animal model. There must be some explanation.
Miljenko
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