Title

Stress-induced Switch in Numb Isoforms Enhances Notch-dependent Expression of Subtype-specific Transient Receptor Potential Channel

Authors

Authors

G. A. Kyriazis; C. Belal; M. Madan; D. G. Taylor; J. Wang; Z. L. Wei; J. V. Pattisapu;S. L. Chan

Comments

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Abbreviated Journal Title

J. Biol. Chem.

Keywords

HIPPOCAMPAL SYNAPTIC PLASTICITY; CAPACITATIVE CALCIUM-ENTRY; AMYLOID; PRECURSOR PROTEIN; STORE-OPERATED CHANNELS; CELL FATE; INTRACELLULAR; DOMAIN; ALZHEIMERS-DISEASE; CORTICAL-NEURONS; MAMMALIAN NUMB; PTB DOMAIN; Biochemistry & Molecular Biology

Abstract

The Notch signaling pathway plays an essential role in the regulation of cell specification by controlling differentiation, proliferation, and apoptosis. Numb is an intrinsic regulator of the Notch pathway and exists in four alternative splice variants that differ in the length of their phosphotyrosine-binding domain (PTB) and proline-rich region domains. The physiological relevance of the existence of the Numb splice variants and their exact regulation are still poorly understood. We previously reported that Numb switches from isoforms containing the insertion in PTB to isoforms lacking this insertion in neuronal cells subjected to trophic factor withdrawal (TFW). The functional relevance of the TFW-induced switch in Numb isoforms is not known. Here we provide evidence that the TFW-induced switch in Numb isoforms regulates Notch signaling strength and Notch target gene expression. PC12 cells stably overexpressing Numbisoforms lacking the PTB insertion exhibited higher basal Notch activity and Notch-dependent transcription of the transient receptor potential channel 6 (TRPC6) when compared with those overexpressing Numb isoforms with the PTB insertion. The differential regulation of TRPC6 expression is correlated with perturbed calcium signaling and increased neuronal vulnerability to TFW-induced death. Pharmacological inhibition of the Notch pathway or knockdown of TRPC6 function ameliorates the adverse effects caused by the TFW-induced switch in Numb isoforms. Taken together, our results indicate that Notch and Numb interaction may influence the sensitivity of neuronal cells to injurious stimuli by modulating calcium-dependent apoptotic signaling cascades.

Journal Title

Journal of Biological Chemistry

Volume

285

Issue/Number

9

Publication Date

1-1-2010

Document Type

Article

Language

English

First Page

6811

Last Page

6825

WOS Identifier

WOS:000275367500084

ISSN

0021-9258

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