APC and Smad7 link TGF? type I receptors to the microtubule system to promote cell migration.

ABSTRACT: Cell migration occurs by activation of complex regulatory pathways that are spatially and temporally integrated in response to extracellular cues. Binding of adenomatous polyposis coli (APC) to the microtubule plus ends in polarized cells is regulated by glycogen synthase kinase 3? (GSK-3?). This event is crucial for establishment of cell polarity during directional migration. However, the role of APC for cellular extension in response to extracellular signals is less clear. Smad7 is a direct target gene for transforming growth factor-? (TGF?) and is known to inhibit various TGF?-induced responses. Here we report a new function for Smad7. We show that Smad7 and p38 mitogen-activated protein kinase together regulate the expression of APC and cell migration in prostate cancer cells in response to TGF? stimulation. In addition, Smad7 forms a complex with APC and acts as an adaptor protein for p38 and GSK-3? kinases to facilitate local TGF?/p38-dependent inactivation of GSK-3?, accumulation of ?-catenin, and recruitment of APC to the microtubule plus end in the leading edge of migrating prostate cancer cells. Moreover, the Smad7-APC complex links the TGF? type I receptor to the microtubule system to regulate directed cellular extension and migratory responses evoked by TGF?.

SUBMITTER: Ekman M 

PROVIDER: S-EPMC3364175 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature