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Bradshaw NJ, Soares DC, Carlyle BC, Ogawa F, Davidson-Smith H, Christie S, Mackie S, Thomson PA, Porteous DJ, Millar JK. PKA phosphorylation of NDE1 is DISC1/PDE4 dependent and modulates its interaction with LIS1 and NDEL1. J Neurosci. 2011 Jun 15 ; 31(24):9043-54. Pubmed Abstract

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Primary Papers: PKA phosphorylation of NDE1 is DISC1/PDE4 dependent and modulates its interaction with LIS1 and NDEL1.

Comment by:  Atsushi Kamiya
Submitted 12 August 2011
Posted 12 August 2011

This paper from Millar and Porteousís group (Bradshaw et al., 2011) proposes a mechanistic link between PDE4 and the NDE1/NDEL1/LIS1 protein complex via a DISC1 pathway. The data suggested that the PKA phosphorylation of NDE1 modulates the protein binding among NDE1, NDEL1, and LIS1, which is regulated by DISC1-PDE4 interaction. Importantly, the authors specified threonine 131 (T131) of NDE1 as a PKA phosphorylation site and produced a phospho-NDE1-T131 antibody. Thus, the question arising is, What is the effect of the phosphorylation of NDE1 at T131 for brain development? Of interest, the authors observed the accumulation of phosphorylated NDE1 at T131 in the centrosome, spindle pole, and intercellular bridge in mitotic cells, as well as in the post-synaptic density in primary hippocampal neurons. The role for the phosphorylation of NDE1 for neuronal processes, such as cell proliferation, differentiation, and synaptic function, is expected to be studied in vivo.

Another question is whether the phosphorylation of NDE1 at T131 is involved in the pathophysiologies of major mental disorders, such as schizophrenia. As the authors stated, DISC1, PDE4, NDE1, and NDEL1, are all genes that have been implicated as genetic risk factors for major psychiatric conditions. Our group has recently reported that phosphorylated DISC1 at S710 is the critical switch signaling from cell proliferation to neuronal migration in the developing brain (Ishizuka et al., 2011). The phosphorylation status of both DISC1 and NDE1 could be characterized in patient-derived cells, such as iPS and iN cells, which might in turn identify biological markers for major mental disorders.

References:

Bradshaw NJ, Soares DC, Carlyle BC, Ogawa F, Davidson-Smith H, Christie S, Mackie S, Thomson PA, Porteous DJ, Millar JK. PKA phosphorylation of NDE1 is DISC1/PDE4 dependent and modulates its interaction with LIS1 and NDEL1. J Neurosci . 2011 Jun 15 ; 31(24):9043-54. Abstract

Ishizuka K, Kamiya A, Oh EC, Kanki H, Seshadri S, Robinson JF, Murdoch H, Dunlop AJ, Kubo K, Furukori K, Huang B, Zeledon M, Hayashi-Takagi A, Okano H, Nakajima K, Houslay MD, Katsanis N, Sawa A. DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature . 2011 May 5 ; 473(7345):92-6. Abstract

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