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Molecular and Cellular Biology, June 2004, p. 4613-4626, Vol. 24, No. 11
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.11.4613-4626.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mitochondrial AKAP121 Binds and Targets Protein Tyrosine Phosphatase D1, a Novel Positive Regulator of src Signaling

Luca Cardone,^1, Annalisa Carlucci,^1, Adele Affaitati,¹ Alessandra Livigni,¹ Tiziana deCristofaro,¹ Corrado Garbi,¹ Stelio Varrone,¹ Axel Ullrich,² Max E. Gottesman,³ Enrico V. Avvedimento,¹ and Antonio Feliciello^1*

Dipartimento di Biologia e Patologia Molecolare e Cellulare, BioGeM Consortium, Istituto di Endocrinologia ed Oncologia Sperimentale CNR, Università "Federico II," 80131 Naples, Italy,¹ Institute of Cancer Research, Columbia University, New York, New York 10032,³ Department of Molecular Biology, Max-Planck-Institut fur Biochemie, D-82152 Martinsried, Germany²

Received 5 December 2003/ Returned for modification 3 February 2004/ Accepted 25 February 2004

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 p38 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.

We dedicate this paper to the memory of Stelio Varrone, an everlasting friend and remarkable mentor.

L.C. and A.C. contributed equally to this work.

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