Mitochondrial AKAP121 binds and targets protein tyrosine phosphatase D1, a novel positive regulator of src signaling

Luca Cardone, Annalisa Carlucci, Adele Affaitati, Alessandra Livigni, Tiziana DeCristofaro, Corrado Garbi, Stelio Varrone, Axel Ullrich, Max E. Gottesman, Enrico V. Avvedimento, Antonio Feliciello

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

A-kinase anchor protein 121 (AKAP121) and its spliced isoform AKAP84 anchor protein kinase A (PKA) to the outer membrane of mitochondria, focusing and enhancing cyclic AMP signal transduction to the organelle. We find that AKAP121/84 also binds PTPD1, a src-associated protein tyrosine phosphatase. A signaling complex containing AKAP121, PKA, PTPD1, and src is assembled in vivo. PTPD1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (EGF) signaling. EGF receptor phosphorylation and downstream activation of ERK 1/2 and Elk1-dependent gene transcription are enhanced by PTPD1. Expression of a PTPD1 mutant lacking catalytic activity inhibits src and downregulates ERK 1/2 but does not affect the activity of c-Jun N-terminal kinase 1/2 and p38α mitogen-activated protein kinase. AKAP121 binds to and redistributes PTPD1 from the cytoplasm to mitochondria and inhibits EGF signaling. Our findings indicate that PTPD1 is a novel positive regulator of src signaling and a key component of the EGF transduction pathway. By binding and/or targeting the phosphatase on mitochondria, AKAP121 modulates the amplitude and persistence of src-dependent EGF transduction pathway. This represents the first example of physical and functional interaction between AKAPs and a protein tyrosine phosphatase.

Original languageEnglish
Pages (from-to)4613-4626
Number of pages14
JournalMolecular and Cellular Biology
Volume24
Issue number11
DOIs
Publication statusPublished - Jun 2004

Fingerprint

A Kinase Anchor Proteins
Protein Tyrosine Phosphatases
Mitochondrial Proteins
Epidermal Growth Factor
Mitochondria
Cyclic AMP-Dependent Protein Kinases
Mitogen-Activated Protein Kinase 9
Mitogen-Activated Protein Kinase 8
src-Family Kinases
p38 Mitogen-Activated Protein Kinases
Phosphoric Monoester Hydrolases
Epidermal Growth Factor Receptor
Organelles
Cyclic AMP
Signal Transduction
Protein Isoforms
Cytoplasm
Down-Regulation
Phosphorylation
Membranes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Cardone, L., Carlucci, A., Affaitati, A., Livigni, A., DeCristofaro, T., Garbi, C., ... Feliciello, A. (2004). Mitochondrial AKAP121 binds and targets protein tyrosine phosphatase D1, a novel positive regulator of src signaling. Molecular and Cellular Biology, 24(11), 4613-4626. https://doi.org/10.1128/MCB.24.11.4613-4626.2004

Mitochondrial AKAP121 binds and targets protein tyrosine phosphatase D1, a novel positive regulator of src signaling. / Cardone, Luca; Carlucci, Annalisa; Affaitati, Adele; Livigni, Alessandra; DeCristofaro, Tiziana; Garbi, Corrado; Varrone, Stelio; Ullrich, Axel; Gottesman, Max E.; Avvedimento, Enrico V.; Feliciello, Antonio.

In: Molecular and Cellular Biology, Vol. 24, No. 11, 06.2004, p. 4613-4626.

Research output: Contribution to journalArticle

Cardone, L, Carlucci, A, Affaitati, A, Livigni, A, DeCristofaro, T, Garbi, C, Varrone, S, Ullrich, A, Gottesman, ME, Avvedimento, EV & Feliciello, A 2004, 'Mitochondrial AKAP121 binds and targets protein tyrosine phosphatase D1, a novel positive regulator of src signaling', Molecular and Cellular Biology, vol. 24, no. 11, pp. 4613-4626. https://doi.org/10.1128/MCB.24.11.4613-4626.2004
Cardone, Luca ; Carlucci, Annalisa ; Affaitati, Adele ; Livigni, Alessandra ; DeCristofaro, Tiziana ; Garbi, Corrado ; Varrone, Stelio ; Ullrich, Axel ; Gottesman, Max E. ; Avvedimento, Enrico V. ; Feliciello, Antonio. / Mitochondrial AKAP121 binds and targets protein tyrosine phosphatase D1, a novel positive regulator of src signaling. In: Molecular and Cellular Biology. 2004 ; Vol. 24, No. 11. pp. 4613-4626.
@article{e24c46ba7e1e4d748050c5bd62aae17d,
title = "Mitochondrial AKAP121 binds and targets protein tyrosine phosphatase D1, a novel positive regulator of src signaling",
abstract = "A-kinase anchor protein 121 (AKAP121) and its spliced isoform AKAP84 anchor protein kinase A (PKA) to the outer membrane of mitochondria, focusing and enhancing cyclic AMP signal transduction to the organelle. We find that AKAP121/84 also binds PTPD1, a src-associated protein tyrosine phosphatase. A signaling complex containing AKAP121, PKA, PTPD1, and src is assembled in vivo. PTPD1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (EGF) signaling. EGF receptor phosphorylation and downstream activation of ERK 1/2 and Elk1-dependent gene transcription are enhanced by PTPD1. Expression of a PTPD1 mutant lacking catalytic activity inhibits src and downregulates ERK 1/2 but does not affect the activity of c-Jun N-terminal kinase 1/2 and p38α mitogen-activated protein kinase. AKAP121 binds to and redistributes PTPD1 from the cytoplasm to mitochondria and inhibits EGF signaling. Our findings indicate that PTPD1 is a novel positive regulator of src signaling and a key component of the EGF transduction pathway. By binding and/or targeting the phosphatase on mitochondria, AKAP121 modulates the amplitude and persistence of src-dependent EGF transduction pathway. This represents the first example of physical and functional interaction between AKAPs and a protein tyrosine phosphatase.",
author = "Luca Cardone and Annalisa Carlucci and Adele Affaitati and Alessandra Livigni and Tiziana DeCristofaro and Corrado Garbi and Stelio Varrone and Axel Ullrich and Gottesman, {Max E.} and Avvedimento, {Enrico V.} and Antonio Feliciello",
year = "2004",
month = "6",
doi = "10.1128/MCB.24.11.4613-4626.2004",
language = "English",
volume = "24",
pages = "4613--4626",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "11",

}

TY - JOUR

T1 - Mitochondrial AKAP121 binds and targets protein tyrosine phosphatase D1, a novel positive regulator of src signaling

AU - Cardone, Luca

AU - Carlucci, Annalisa

AU - Affaitati, Adele

AU - Livigni, Alessandra

AU - DeCristofaro, Tiziana

AU - Garbi, Corrado

AU - Varrone, Stelio

AU - Ullrich, Axel

AU - Gottesman, Max E.

AU - Avvedimento, Enrico V.

AU - Feliciello, Antonio

PY - 2004/6

Y1 - 2004/6

N2 - A-kinase anchor protein 121 (AKAP121) and its spliced isoform AKAP84 anchor protein kinase A (PKA) to the outer membrane of mitochondria, focusing and enhancing cyclic AMP signal transduction to the organelle. We find that AKAP121/84 also binds PTPD1, a src-associated protein tyrosine phosphatase. A signaling complex containing AKAP121, PKA, PTPD1, and src is assembled in vivo. PTPD1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (EGF) signaling. EGF receptor phosphorylation and downstream activation of ERK 1/2 and Elk1-dependent gene transcription are enhanced by PTPD1. Expression of a PTPD1 mutant lacking catalytic activity inhibits src and downregulates ERK 1/2 but does not affect the activity of c-Jun N-terminal kinase 1/2 and p38α mitogen-activated protein kinase. AKAP121 binds to and redistributes PTPD1 from the cytoplasm to mitochondria and inhibits EGF signaling. Our findings indicate that PTPD1 is a novel positive regulator of src signaling and a key component of the EGF transduction pathway. By binding and/or targeting the phosphatase on mitochondria, AKAP121 modulates the amplitude and persistence of src-dependent EGF transduction pathway. This represents the first example of physical and functional interaction between AKAPs and a protein tyrosine phosphatase.

AB - A-kinase anchor protein 121 (AKAP121) and its spliced isoform AKAP84 anchor protein kinase A (PKA) to the outer membrane of mitochondria, focusing and enhancing cyclic AMP signal transduction to the organelle. We find that AKAP121/84 also binds PTPD1, a src-associated protein tyrosine phosphatase. A signaling complex containing AKAP121, PKA, PTPD1, and src is assembled in vivo. PTPD1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (EGF) signaling. EGF receptor phosphorylation and downstream activation of ERK 1/2 and Elk1-dependent gene transcription are enhanced by PTPD1. Expression of a PTPD1 mutant lacking catalytic activity inhibits src and downregulates ERK 1/2 but does not affect the activity of c-Jun N-terminal kinase 1/2 and p38α mitogen-activated protein kinase. AKAP121 binds to and redistributes PTPD1 from the cytoplasm to mitochondria and inhibits EGF signaling. Our findings indicate that PTPD1 is a novel positive regulator of src signaling and a key component of the EGF transduction pathway. By binding and/or targeting the phosphatase on mitochondria, AKAP121 modulates the amplitude and persistence of src-dependent EGF transduction pathway. This represents the first example of physical and functional interaction between AKAPs and a protein tyrosine phosphatase.

UR - http://www.scopus.com/inward/record.url?scp=2442717798&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2442717798&partnerID=8YFLogxK

U2 - 10.1128/MCB.24.11.4613-4626.2004

DO - 10.1128/MCB.24.11.4613-4626.2004

M3 - Article

VL - 24

SP - 4613

EP - 4626

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 11

ER -