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Molecular and Cellular Biology, September 2005, p. 7988-8000, Vol. 25, No. 18
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.18.7988-8000.2005

Epidermal Growth Factor-Dependent Phosphorylation of the GGA3 Adaptor Protein Regulates Its Recruitment to Membranes

Satoshi Kametaka, Rafael Mattera, and Juan S. Bonifacino*

Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Received 11 February 2005/ Returned for modification 6 March 2005/ Accepted 25 June 2005

The Golgi-localized, Gamma-ear-containing, Arf-binding (GGA) proteins are monomeric clathrin adaptors that mediate the sorting of transmembrane cargo at the trans-Golgi network and endosomes. Here we report that one of these proteins, GGA3, becomes transiently phosphorylated upon activation of the epidermal growth factor (EGF) receptor. This phosphorylation takes place on a previously unrecognized site in the "hinge" segment of the protein, S368, and is strictly dependent on the constitutive phosphorylation of another site, S372. The EGF-induced phosphorylation of S368 does not require internalization of the EGF receptor or association of GGA3 with membranes. This phosphorylation can be blocked by inhibitors of both the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways that function downstream of the activated EGF receptor. Phosphorylation of GGA3 on S368 causes an increase in the hydrodynamic radius of the protein, indicating a transition to a more asymmetric shape. Mutation of S368 and S372 to a phosphomimic aspartate residue decreases the association of GGA3 with membranes. These observations indicate that EGF signaling elicits phosphorylation events that regulate the association of GGA3 with organellar membranes.

* Corresponding author. Mailing address: Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Building 18T/Room 101, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-6368. Fax: (301) 402-0078. E-mail: Juan{at}helix.nih.gov.

Molecular and Cellular Biology, September 2005, p. 7988-8000, Vol. 25, No. 18
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.18.7988-8000.2005




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