Activation of Protein Kinase C alpha Is Necessary for Sorting the PDGF beta-Receptor to Rab4a-dependent Recycling

Research output: Contribution to journalArticle

Authors

Colleges, School and Institutes

Abstract

Previous studies showed that loss of the T-cell protein tyrosine phosphatase (TC-PTP) induces Rab4a-dependent recycling of the platelet-derived growth factor (PDGF) beta-receptor in mouse embryonic fibroblasts (MEFs). Here we identify protein kinase C (PKC) alpha as the critical signaling component that regulates the sorting of the PDGF beta-receptor at the early endosomes. Down-regulation of PKC abrogated receptor recycling by preventing the sorting of the activated receptor into EGFP-Rab4a positive domains on the early endosomes. This effect was mimicked by inhibition of PKC alpha, using myristoylated inhibitory peptides or by knockdown of PKC alpha with shRNAi. In wt MEFs, short-term preactivation of PKC by PMA caused a ligand-induced PDGF beta-receptor recycling that was dependent on Rab4a function. Together, these observations demonstrate that PKC activity is necessary for recycling of ligand-stimulated PDGF beta-receptor to occur. The sorting also required Rab4a function as it was prevented by expression of EGFP-Rab4aS22N. Preventing receptor sorting into recycling endosomes increased the rate of receptor degradation, indicating that the sorting of activated receptors at early endosomes directly regulates the duration of receptor signaling. Activation of PKC through the LPA receptor also induced PDGF beta-receptor recycling and potentiated the chemotactic response to PDGF-BB. Taken together, our present findings indicate that sorting of PDGF beta-receptors on early endosomes is regulated by sequential activation of PKC alpha and Rab4a and that this sorting step could constitute a point of cross-talk with other receptors.

Details

Original languageEnglish
Pages (from-to)2856-2863
Number of pages8
JournalMolecular Biology of the Cell
Volume20
Issue number12
Publication statusPublished - 1 Jun 2009