Mitochondrial AKAP121 binds and targets protein tyrosine phosphatase D1, a novel positive regulator of src signaling.
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 p38alpha 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.
Cardone
Luca
L
Dipartimento di Biologia e Patologia Molecolare e Cellulare, via S. Pansini, 5, 80131 Naples, Italy. feliciel@unina.it
Carlucci
Annalisa
A
Affaitati
Adele
A
Livigni
Alessandra
A
DeCristofaro
Tiziana
T
Garbi
Corrado
C
Varrone
Stelio
S
Ullrich
Axel
A
Gottesman
Max E
ME
Avvedimento
Enrico V
EV
Feliciello
Antonio
A
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D015398:Signal Transduction / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism*
D054758:A Kinase Anchor Proteins; C105137:AKAP1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D020033:Protein Isoforms; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019061:src-Family Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; C409985:PTPN21 protein, human; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor