Neurotrophin signaling plays important roles in regulating the survival, differentiation and maintenance of neurons in the nervous system. Binding of neurotrophins to their cognate receptors tropomyosin related kinases (Trks) induces transactivation and phosphorylation of the receptor at several tyrosine residues. These phosphorylated tyrosine residues then serve as crucial docking sites for adaptor proteins, which upon association with the receptor initiates multiple signaling events to mediate the action of neurotrophins. Recently, recruitment of adaptor molecules has also been observed to modulate the signaling cascade downstream of Trk activation. Here we report the characterization of two signaling regulators implicated in the regulation of neurotrophin-mediated Trk signaling: SLAM...[ Read more ]

Neurotrophin signaling plays important roles in regulating the survival, differentiation and maintenance of neurons in the nervous system. Binding of neurotrophins to their cognate receptors tropomyosin related kinases (Trks) induces transactivation and phosphorylation of the receptor at several tyrosine residues. These phosphorylated tyrosine residues then serve as crucial docking sites for adaptor proteins, which upon association with the receptor initiates multiple signaling events to mediate the action of neurotrophins. Recently, recruitment of adaptor molecules has also been observed to modulate the signaling cascade downstream of Trk activation. Here we report the characterization of two signaling regulators implicated in the regulation of neurotrophin-mediated Trk signaling: SLAM-associated protein (SAP) and cyclin-dependent kinase 5 (Cdk5). Using yeast two-hybrid screen, we identified a SH-2 domain-containing molecule, SAP, as an interacting protein of TrkB. SAP was initially identified as an adaptor molecule in Slam family receptor signaling for regulating interferon gamma (IFN-γ) secretion. In the current study, we found that SAP interacted with TrkA, B and C receptors in vitro and in vivo. Binding of SAP required Trk receptor activation and phosphorylation at the tyrosine 674 residue, which is located in the activation loop of the kinase domain. Overexpression of SAP with Trk attenuated tyrosine phosphorylation of the receptors, and reduced the binding of src homology 2-B (SH2B) and SH2-containing collagen-related protein (Shc) to TrkB. Moreover, overexpression of SAP in PC12 cells suppressed the nerve growth factor (NGF)-dependent activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and phospholipase C gamma (PLCγ), in addition to inhibiting neurite outgrowth. Our findings therefore demonstrated that SAP may serve as a negative regulator of Trk receptor activation and downstream signaling. In addition, we recently observed that cyclin-dependent kinase 5 (Cdk5) associates with TrkB receptor, implicating a novel role of Cdk5 in modulating TrkB signaling. Inhibition of Cdk5 activity in primary cortical neuron culture resulted in upregulation of brain-derived neurotrophic factor (BDNF)-induced ERK 1/2, ERK5, p70S6K and cAMP response element-binding protein (CREB) phosphorylation. ERK5 and CREB phosphorylation was also elevated in Cdk5-deficient brain. Taken together, our data revealed that Cdk5 may also participate in modulation of BDNF-induced TrkB signaling.

Paper reporting some of the findings in this study:

Lo, K.Y., Chin, W.H., Ng, Y.P., Cheng, A.W., Cheung, Z.H., and Ip, N.Y. (2005). SLAM-associated protein (SAP) as a potential negative regulator in Trk signaling. J. Biol. Chem. (Under revision).

Ng, Y.P., LO, K.Y., Cheung, Z.H., and IP, N.Y. (2005). Signaling through the neurotrophin receptors in the nervous systems. Handbook of Neurochemistry and Molecular Neuro biology, 3rd ed. 9, (In press).