Numb isoforms containing a short PTB domain promote neurotrophic factor-induced differentiation and neurotrophic factor withdrawal-induced death of PC12 cells

Ward A. Pedersen, Sic L. Chan, Haiyan Zhu, Lilanie A. Abdur-Rahman, Joseph M. Verdi, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

The development of the nervous system is regulated by trophic signals that control cell proliferation, differentiation, and survival. Numb is an evolutionarily conserved protein identified by its ability to control cell fate in the nervous system of Drosophila. Mammals express four isoforms of Numb that differ in the length of a phosphotyrosine-binding (PTB) domain and a proline-rich region (PRR). Using PC12 cells stably expressing each of the human isoforms, we show that Numb regulates sensitivity of the cells to neurotrophic factor-induced differentiation and neurotrophic factor withdrawal-induced death in an isoform-specific manner. Numb isoforms containing a short PTB domain enhance the differentiation response to NGF and enhance apoptosis upon NGF withdrawal; Numb isoforms containing a long PTB domain exhibit the same sensitivity to NGF as vector-transfected cells. These effects of Numb were found to be independent of the length of the PRR. In undifferentiated conditions, the levels of full-length TrkA and of phosphorylated p44/p42 mitogen-activated protein kinase (MAPK) are increased in cells expressing Numb isoforms with a short PTB domain, indicating an up-regulation of NGF signaling pathways. Furthermore, we provide evidence that the mechanism whereby short PTB domain Numb isoforms sensitize cells to trophic factor deprivation-induced apoptosis involves elevations in intracellular calcium concentrations. Our results suggest that Numb sensitizes cells to neurotrophin responses in an isoform-specific manner, an effect that may play an important role in the development and plasticity of the nervous system.

Original languageEnglish (US)
Pages (from-to)976-986
Number of pages11
JournalJournal of Neurochemistry
Volume82
Issue number4
DOIs
StatePublished - Aug 2002

Fingerprint

Phosphotyrosine
PC12 Cells
Nerve Growth Factors
Protein Isoforms
Nerve Growth Factor
Neurology
Nervous System
Proline
Apoptosis
Mammals
Mitogen-Activated Protein Kinase 1
Cell proliferation
Drosophila
Plasticity
Cell Differentiation
Cell Survival
Up-Regulation
Cells
Cell Proliferation
Calcium

Keywords

  • Apoptosis
  • MAP kinase
  • Neurite outgrowth
  • Phosphotyrosine-binding domain
  • Proline-rich region
  • TrkA

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Numb isoforms containing a short PTB domain promote neurotrophic factor-induced differentiation and neurotrophic factor withdrawal-induced death of PC12 cells. / Pedersen, Ward A.; Chan, Sic L.; Zhu, Haiyan; Abdur-Rahman, Lilanie A.; Verdi, Joseph M.; Mattson, Mark P.

In: Journal of Neurochemistry, Vol. 82, No. 4, 08.2002, p. 976-986.

Research output: Contribution to journalArticle

Pedersen, Ward A. ; Chan, Sic L. ; Zhu, Haiyan ; Abdur-Rahman, Lilanie A. ; Verdi, Joseph M. ; Mattson, Mark P. / Numb isoforms containing a short PTB domain promote neurotrophic factor-induced differentiation and neurotrophic factor withdrawal-induced death of PC12 cells. In: Journal of Neurochemistry. 2002 ; Vol. 82, No. 4. pp. 976-986.
@article{e09eeb5589c640dcac7c3ab488661be7,
title = "Numb isoforms containing a short PTB domain promote neurotrophic factor-induced differentiation and neurotrophic factor withdrawal-induced death of PC12 cells",
abstract = "The development of the nervous system is regulated by trophic signals that control cell proliferation, differentiation, and survival. Numb is an evolutionarily conserved protein identified by its ability to control cell fate in the nervous system of Drosophila. Mammals express four isoforms of Numb that differ in the length of a phosphotyrosine-binding (PTB) domain and a proline-rich region (PRR). Using PC12 cells stably expressing each of the human isoforms, we show that Numb regulates sensitivity of the cells to neurotrophic factor-induced differentiation and neurotrophic factor withdrawal-induced death in an isoform-specific manner. Numb isoforms containing a short PTB domain enhance the differentiation response to NGF and enhance apoptosis upon NGF withdrawal; Numb isoforms containing a long PTB domain exhibit the same sensitivity to NGF as vector-transfected cells. These effects of Numb were found to be independent of the length of the PRR. In undifferentiated conditions, the levels of full-length TrkA and of phosphorylated p44/p42 mitogen-activated protein kinase (MAPK) are increased in cells expressing Numb isoforms with a short PTB domain, indicating an up-regulation of NGF signaling pathways. Furthermore, we provide evidence that the mechanism whereby short PTB domain Numb isoforms sensitize cells to trophic factor deprivation-induced apoptosis involves elevations in intracellular calcium concentrations. Our results suggest that Numb sensitizes cells to neurotrophin responses in an isoform-specific manner, an effect that may play an important role in the development and plasticity of the nervous system.",
keywords = "Apoptosis, MAP kinase, Neurite outgrowth, Phosphotyrosine-binding domain, Proline-rich region, TrkA",
author = "Pedersen, {Ward A.} and Chan, {Sic L.} and Haiyan Zhu and Abdur-Rahman, {Lilanie A.} and Verdi, {Joseph M.} and Mattson, {Mark P.}",
year = "2002",
month = "8",
doi = "10.1046/j.1471-4159.2002.01036.x",
language = "English (US)",
volume = "82",
pages = "976--986",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - Numb isoforms containing a short PTB domain promote neurotrophic factor-induced differentiation and neurotrophic factor withdrawal-induced death of PC12 cells

AU - Pedersen, Ward A.

AU - Chan, Sic L.

AU - Zhu, Haiyan

AU - Abdur-Rahman, Lilanie A.

AU - Verdi, Joseph M.

AU - Mattson, Mark P.

PY - 2002/8

Y1 - 2002/8

N2 - The development of the nervous system is regulated by trophic signals that control cell proliferation, differentiation, and survival. Numb is an evolutionarily conserved protein identified by its ability to control cell fate in the nervous system of Drosophila. Mammals express four isoforms of Numb that differ in the length of a phosphotyrosine-binding (PTB) domain and a proline-rich region (PRR). Using PC12 cells stably expressing each of the human isoforms, we show that Numb regulates sensitivity of the cells to neurotrophic factor-induced differentiation and neurotrophic factor withdrawal-induced death in an isoform-specific manner. Numb isoforms containing a short PTB domain enhance the differentiation response to NGF and enhance apoptosis upon NGF withdrawal; Numb isoforms containing a long PTB domain exhibit the same sensitivity to NGF as vector-transfected cells. These effects of Numb were found to be independent of the length of the PRR. In undifferentiated conditions, the levels of full-length TrkA and of phosphorylated p44/p42 mitogen-activated protein kinase (MAPK) are increased in cells expressing Numb isoforms with a short PTB domain, indicating an up-regulation of NGF signaling pathways. Furthermore, we provide evidence that the mechanism whereby short PTB domain Numb isoforms sensitize cells to trophic factor deprivation-induced apoptosis involves elevations in intracellular calcium concentrations. Our results suggest that Numb sensitizes cells to neurotrophin responses in an isoform-specific manner, an effect that may play an important role in the development and plasticity of the nervous system.

AB - The development of the nervous system is regulated by trophic signals that control cell proliferation, differentiation, and survival. Numb is an evolutionarily conserved protein identified by its ability to control cell fate in the nervous system of Drosophila. Mammals express four isoforms of Numb that differ in the length of a phosphotyrosine-binding (PTB) domain and a proline-rich region (PRR). Using PC12 cells stably expressing each of the human isoforms, we show that Numb regulates sensitivity of the cells to neurotrophic factor-induced differentiation and neurotrophic factor withdrawal-induced death in an isoform-specific manner. Numb isoforms containing a short PTB domain enhance the differentiation response to NGF and enhance apoptosis upon NGF withdrawal; Numb isoforms containing a long PTB domain exhibit the same sensitivity to NGF as vector-transfected cells. These effects of Numb were found to be independent of the length of the PRR. In undifferentiated conditions, the levels of full-length TrkA and of phosphorylated p44/p42 mitogen-activated protein kinase (MAPK) are increased in cells expressing Numb isoforms with a short PTB domain, indicating an up-regulation of NGF signaling pathways. Furthermore, we provide evidence that the mechanism whereby short PTB domain Numb isoforms sensitize cells to trophic factor deprivation-induced apoptosis involves elevations in intracellular calcium concentrations. Our results suggest that Numb sensitizes cells to neurotrophin responses in an isoform-specific manner, an effect that may play an important role in the development and plasticity of the nervous system.

KW - Apoptosis

KW - MAP kinase

KW - Neurite outgrowth

KW - Phosphotyrosine-binding domain

KW - Proline-rich region

KW - TrkA

UR - http://www.scopus.com/inward/record.url?scp=0036678724&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036678724&partnerID=8YFLogxK

U2 - 10.1046/j.1471-4159.2002.01036.x

DO - 10.1046/j.1471-4159.2002.01036.x

M3 - Article

C2 - 12358803

AN - SCOPUS:0036678724

VL - 82

SP - 976

EP - 986

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 4

ER -