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Published ahead of print on February 23, 2006, doi:10.1165/rcmb.2006-0044OC

Am. J. Respir. Cell Mol. Biol., Volume 35, Number 1, July 2006, 127-132

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Submitted on January 30, 2006
Revised on February 22, 2006

GPCR- as well as ROS-dependent Phosphorylation of AP2µ2 is Essential for Na+,K+-ATPase Endocytosis

Zongpei Chen1, Rafael T Krmar1, Laura Dada2, Riad Efendiev3, Ingo B Leibiger4, Carlos H Pedemonte3, Adrian I Katz5, Jacob I Sznajder2, and Alejandro M Bertorello1*

1 Department of Medicine, Atherosclerosis Research Unit, Membrane Signaling Networks, Karolinska University, Karolinska Institutet, Stockholm, Sweden, 2 Department of Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA, 3 Department of Pharmacological and Pharmaceutical Sciences, University of Houston, College of Pharmacy, Houston, TX, USA, 4 Department of Molecular Medicine, Rolf Luft Center for Diabetes Research, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden, 5 Department of Medicine, University of Chicago, Chicago, IL, USA

* To whom correspondence should be addressed. E-mail: alejandro.bertorello{at}medks.ki.se.

Activation of GPCR by dopamine as well as hypoxia- generated reactive oxygen species promote Na+,K+-ATPase endocytosis. This effect is clathrin dependent and involves the activation of PKC-{zeta} and phosphorylation of the Na+,K+-ATPase {alpha}-subunit. Because incorporation of cargo into clathrin vesicles required its association with adaptor proteins, we studied whether phosphorylation of adaptor protein-2 plays a role in its binding to the Na+,K+-ATPase {alpha}-subunit and thereby in its endocytosis. Dopamine induces a time-dependent phosphorylation of adaptor protein -2 µ2 subunit. Using specific inhibitors and dominant negative mutants it was established that this effect was mediated by activation of the AAK1/PKC-{zeta} isoform. Expression of the AP-2 µ2 bearing a mutation in its phosphorylation site (T156A) prevented Na+,K+-ATPase endocytosis and changes in activity induced by dopamine. Similarly, in lung alveolar epithelial cells hypoxia-induced endocytosis of Na+,K+-ATPase requires the binding of AP-2 to the tyrosine based motif (Tyr-537) located in the Na+,K+-ATPase {alpha}-subunit, and this effect requires phosphorylation of the AP-2 µ2 subunit. It is therefore concluded that phosphorylation of AP-2 µ2 subunit is essential for Na+,K+-ATPase endocytosis in response to a variety of signals, such as dopamine and reactive oxygen species.




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