A Kinase-Free BDNF Signaling Mechanism

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Science's STKE  15 Feb 2005:
Vol. 2005, Issue 271, pp. tw63
DOI: 10.1126/stke.2712005tw63

Brain-derived neurotrophic factor (BDNF) signals through TrkB receptors to affect neuronal survival and differentiation as well as synaptic plasticity. Although full-length TrkB acts as a receptor tyrosine kinase, two truncated isoforms with distinct C termini that lack kinase activity have also been described that have been hypothesized to act as endogenous dominant negatives that inhibit signaling through the full-length isoform; alternatively, they may signal independently of it. Ohira et al. used the C-terminal sequence of one of these truncated isoforms (T1) to affinity purify a 28-kD T1-binding protein from the cytosolic fraction of adult rat brains, which they identified as Rho GDP dissociation inhibitor 1 (GDI1). GDI1, which binds Rho guanosine triphosphatases and inhibits GDP dissociation (thereby stabilizing their inactive form), bound T1 in an in vitro assay and coimmunoprecipitated with T1 that was transfected into HEK293 cells. Of the known receptors for BDNF, only T1 was expressed in long-term primary astrocyte cultures from neonatal rat hippocampus or cortical astrocytes in the adult rat brain. BDNF promoted T1 dissociation from GDI1 in long-term cultures of astrocytes; inhibited the activity of the GDI1 substrates RhoA, Cdc42, and Rac1; and elicited a change in astrocyte morphology from a fibrous to a flattened shape. Transfection of T1 or a deletion mutant into short-term astrocyte cultures (which did not express endogenous T1) confirmed that the effects of BDNF on Rho GTPase activity and morphology depended on T1. Thus, BDNF can signal directly through T1 to affect Rho GTPase activity and thereby astrocyte morphology.

K. Ohira, H. Kumanogoh, Y. Sahara, K. J. Homma, H. Hirai, S. Nakamura, M. Hayashi, A truncated tropo-myosine-related kinase B receptor, T1, regulates glial cell morphology via Rho GDP dissociation inhibitor 1. J. Neurosci. 25, 1343-1353 (2005). [Abstract] [Full Text]

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