The PDZ-binding motif of MCC is phosphorylated at position −1 and controls lamellipodia formation in colon epithelial cells

In this study, we describe a new post-translational modification at position −1 of the PDZ-binding motif in the mutated in colorectal cancer (MCC) protein and its role in lamellipodia formation. Serine 828 at position −1 of this motif is phosphorylated, which is predicted to increase MCC binding aff...

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Published in:	Biochimica et biophysica acta 2012-06, Vol.1823 (6), p.1058-1067
Main Authors:	Pangon, Laurent, Van Kralingen, Christa, Abas, Melissa, Daly, Roger J., Musgrove, Elizabeth A., Kohonen-Corish, Maija R.J.
Format:	Article
Language:	eng
Subjects:	Amino Acid Motifs Amino Acid Sequence Amino Acid Substitution - genetics Cell Line, Tumor Cell Membrane - metabolism Cell Polarity Colon - cytology Epithelial Cells - metabolism Humans Lamellipodia MCC Membrane Proteins - chemistry Membrane Proteins - metabolism Molecular Sequence Data Mutant Proteins - chemistry Mutant Proteins - metabolism Mutation - genetics Myosin-IIB Nonmuscle Myosin Type IIB - metabolism PDZ PDZ Domains PDZ-binding motif Phosphorylation Phosphoserine - metabolism Protein Binding Protein Transport Pseudopodia - metabolism Scrib Structure-Activity Relationship Subcellular Fractions - metabolism Tumor Suppressor Proteins - chemistry Tumor Suppressor Proteins - metabolism
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Summary:	In this study, we describe a new post-translational modification at position −1 of the PDZ-binding motif in the mutated in colorectal cancer (MCC) protein and its role in lamellipodia formation. Serine 828 at position −1 of this motif is phosphorylated, which is predicted to increase MCC binding affinity with the polarity protein Scrib. We show that endogenous MCC localizes at the active migratory edge of cells, where it interacts with Scrib and the non-muscle motor protein Myosin-IIB. Expression of MCC harboring a phosphomimetic mutation MCC-S828D strongly impaired lamellipodia formation and resulted in accumulation of Myosin-IIB in the membrane cortex fraction. We propose that MCC regulates lamellipodia formation by binding to Scrib and its downstream partner Myosin-IIB in a multiprotein complex. Importantly, we propose that the function of this complex is under the regulation of a newly described phosphorylation of the PDZ-binding motif at position −1. ► First functional characterization of −1 phosphorylation of the PDZ binding motif. ► Mutation of the S828 phosphosite of MCC disrupts lamellipodia formation. ► Phosphorylation of MCC-S828 is predicted to increase MCC interaction with Scrib. ► MCC also interacts with the non-muscle motor protein Myosin-IIB. ► Mutation of MCC-S828 traps Myosin-IIB in the membrane cortex.
ISSN:	0167-4889 0006-3002 1879-2596 1878-2434