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Signaling by PHLPP1 and PKC alpha : function and specificity


Signaling networks involve multiple layers of regulation. Determination of the essential components of such networks and the ways in which specificity of signaling is ensured is necessary for a full understanding of normal physiology and disease. The studies presented herein focus on signaling by protein kinase C and its negative regulator PHLPP, which are important for cell motility and growth. Though PHLPP1 has previously been shown to directly dephosphorylate numerous kinases that are important for maintaining the balance between proliferation and apoptosis, PHLPP1-null mice did not display substantial changes in the phosphorylation of these factors. Furthermore, these mice developed normally and lacked the expected changes in growth and insulin signaling; this lack of phenotype may be due to compensation by the closely related phosphatase PHLPP2 or other negative regulators of growth. We also showed that PKC[alpha]'s effects on cellular migration in a wound healing assay were dependent on a novel, PDZ ligand-based interaction with the scaffold DLG1. We determined that PKC[alpha] phosphorylates a previously unrecognized site on DLG1 and that PKC[alpha] activity at the scaffold correlates with invasive behavior in lung cancer cells. These data suggest that PKC[alpha] may promote metastasis in a DLG1-dependent manner and highlight the importance of scaffolding interactions for the proper regulation of signaling

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